2,3-disubstituted pyridine derivatives, process for the preparation thereof, drug compositions containing the same and intermediates for the preparation

ABSTRACT

A compound of the formula (I)                    
     wherein A is O, S, CHR 1  or NR 2 , R 1  and R 2  are H, lower alkyl, X 1  and X 2  are H, halogen, nitro, cyano, etc., Y 1  is H, lower alkyl, Z 1  and Z 2  are H, halogen, cyano, hydroxy, lower alkyl, etc., and n is an integer of 2 to 4, a pharmaceutically acceptable salt thereof, a process for preparing the same, a pharmaceutical composition containing the same as an active ingredient, and an intermediate therefor. The compounds (I) of the present invention show a potent PDE IV inhibitory activity as well as an excellent bronchodilating activity, and hence, they are widely useful as a PDE IV inhibitor in the treatment or prophylaxis of allergic inflammatory diseases or organ inflammatory diseases, especially in the treatment or prophylaxis of pulmonary diseases accompanied by airway obstruction such as asthma.

This application is a 371 of PCT/JP99/05385 filed Sep. 30, 1999.

TECHNICAL FIELD

The present invention relates to a novel 2,3-disubstituted pyridinederivative exhibiting a phosphodiesterase IV (hereinafter, referred toas PDE IV) inhibitory activity being useful as a medicament, a processfor the preparation thereof, a pharmaceutical composition containing thesame, and an intermediate therefor.

BACKGROUND ART

Hitherto, theophylline or various chemical mediator antagonists havebeen used as an agent for treatment of asthma, but these agents havedefects, for example, they cannot exhibit a sufficient inhibitory effecton bronchoconstriction or a sufficient effect on airway inflammatory andthey cannot show a sufficient selectivity from their side effects on thecardiovascular system. Steroids also have been used as an agent fortreatment of asthma, and their effects on the airway inflammation arepotent but their inhibitory effects on bronchoconstriction is weak, andin addition, serious side effects of steroids have also been predicted.Therefore, it has been desired to develop a novel agent exhibiting aninhibitory effect on bronchoconstriction as well as an effect on theairway inflammation.

PDE IV widely distributes onto the bronchial smooth muscle andinflammatory cells including eosinophil, and it is an enzyme catalyzingthe destruction of cyclic AMP (hereinafter, occasionally referred to ascAMP). It has widely been known that by inhibiting PDE IV, theconstriction of the bronchial smooth muscle is prevented, and theactivation of inflammatory cells is prevented (Current MedicinalChemistry, vol. 2, p. 561-572 (1995)).

The compounds of the following formulae, for example, Rolipram (U.S.Pat. No. 4,193,926), RP-73401 (WO 92 12961), SB-207499 (WO 93 19749),are exemplified as a representative compound having a PDE IV inhibitoryactivity.

In addition, EP 773024 discloses that an N-substituted nicotinamidecompound of the following formula (A) exhibits a PDE IV inhibitoryactivity.

wherein R³ is 1-piperidyl, phenyl, benzyl, etc., Y is hydrogen, fluoroor chloro, and X is hydrogen, fluoro, chloro, methoxy, trifluoromethyl,cyano, carboxy, methylcarbamoyl, dimethylcarbamoyl or acarbo(C₁-C₄)alkoxy.

In addition, WO 9845268 discloses that a nictoninamide compound of thefollowing formula (B) exhibits a PDE IV inhibitory activity.

wherein m is 0 or 1, n is 0 or 1, o is 0, 1, 2, 3, or 4, p is 0 or 1, qis 0, 1, 2, or 3, r is 0, 1, 2, 3, or 4, t is 0 or 1, A is an oxygenatom, >NH, etc., B is an oxygen atom or NH, D is an oxygen atom or NR⁹,E is CH₂, an oxygen atom, NH or S(O)_(a), R¹ is a hydrogen atom, a(C₁-C₆)alkyl group, a (C₃-C₇)heterocyclic group, etc., R², R³ and R⁴ area hydrogen atom, a hydroxy group, etc., R⁵ is a (C₃-C₇)heterocycle, R⁶,R⁷ and R⁸ are a hydrogen atom, a (C₁-C₆)alkyl group, etc.

However, conventional PDE IV inhibitors cannot show a sufficientbronchodilating activity, and under such circumstances, it has beendesired to develop a novel PDE IV inhibitor exhibiting more potentbronchodilating activity as well as effects on the airway inflammation.

On the other hand, a compound of the above formula (A) or (B) whereinthe 3-substituent of the pyridine ring is a pyridylalkyleneoxy group hasnever been known.

An object of the present invention is to provide a novel2,3-disubstituted pyridine derivative and a pharmaceutically acceptablesalt thereof, which show an excellent PDE IV inhibitory activity.

DISCLOSURE OF INVENTION

The present invention relates to a 2,3-disubstituted pyridine derivativeof the following formula (I) or a pharmaceutically acceptable saltthereof, a phosphodiesterase IV inhibitor containing said compound as anactive ingredient, and a pharmaceutical composition containing the same.

wherein

A is an oxygen atom, a sulfur atom, CHR¹ or NR², R¹ and R² are ahydrogen atom or a lower alkyl group;

X¹ and X² are the same or different and each a hydrogen atom, a halogenatom, a nitro group, a cyano group, a hydroxy group, a lower alkylgroup, a hydroxy-substituted lower alkyl group, a halogeno-lower alkylgroup, a lower alkoxy group, a cyclo-lower alkoxy group, ahydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, alower alkoxy-substituted lower alkoxy group, a carboxy-substituted loweralkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, acarboxyl group, a lower alkoxycarbonyl group, a mono- or di-loweralkylaminocarbonyl group, a lower acyl group, a lower acyloxy group, anamino group, a lower acylamino group, a carbamoyl group, a 5-tetrazolylgroup, or a group which can be converted into a hydroxy group in vivo;

Y¹ is a hydrogen atom or a lower alkyl group;

Z¹ and Z² are the same or different and each a hydrogen atom, a halogenatom, a cyano group, a hydroxy group, a lower alkyl group, ahydroxy-substituted lower alkyl group, a halogeno-lower alkyl group, alower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substitutedlower alkoxy group, a halogeno-lower alkoxy group, a loweralkoxy-substituted lower alkoxy group, a carboxy-substituted loweralkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, acarboxyl group, a lower alkoxycarbonyl group, a mono- or di-loweralkylaminocarbonyl group, a lower acyloxy group, an amino group, a mono-or di-lower alkylamino group, a lower acylamino group, a loweralkoxycarbonylamino group, a lower alkylsulfonylamino group, a carbamoylgroup, a 5-tetrazolyl group, or a group which can be convereted into ahydroxy group in vivo; and

n is an integer of 2 to 4.

The pharmaceutically acceptable salt includes a pharmaceuticallyacceptable acid addition salt, an alkali metal salt, an alkaline earthmetal salt or a salt with an organic base. For example, the acidaddition salt includes a salt with an inorganic acid such ashydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, etc., or asalt with an organic acid such as oxalate, maleate, fumarate, malonate,lactate, malate, citrate, tartrate, benzoate, methanesulfonate,p-toluenesulfonate, gluconate, etc. The alkali metal salt includes, forexample, a salt with an inorganic alkali metal such as sodium salt,potassium salt, and the alkaline earth metal salt includes, for example,calcium salt, magnesium salt. The salt with an organic base includes,for example, a salt with ammonia, methylamine, triethylamine,tributylamine, diisopropylethylamine, N-methylmorpholine,dicyclohexylamine.

The present compound of the formula (I) and a pharmaceuticallyacceptable salt thereof may exist in the form of a hydrate and/or asolvate, and the present invention also includes these hydrates andsolvates as well.

The present compounds of the formula (I) may optionally have one or moreasymmetric carbon atoms, and the present invention also includes thesestereoisomers and a mixture thereof.

When Z¹ or Z² is a hydroxy group and these groups attach to the2-position or the 4-position of the pyridine ring, the present compoundsof the formula (I) may have a keto-enol tautomer, and the presentinvention also includes these tautomers, and a mixture thereof.

In the compound (I), the group being able to be converted into a hydroxygroup in vivo means a group which can be enzymatically ornon-enzymatically destructed to a hydroxy group in vivo, for example,one wherein a hydroxy group is acylated, carbonated or carbamated by anacetyl group, a propionyl group, a benzoyl group, an ethoxycarbonylgroup, a carbamoyl group, an amino acid residue, etc. Hereinafter,compounds having such groups may occasionally be referred as a prodrug.

The present invention also relates to an intermediate for preparing a2,3-disubstituted pyridine derivative of the above formula (I), i.e., apyridine derivative of the following formula (II):

wherein Z³ is a hydrogen atom, a lower alkyl group, a cyclo-lower alkylgroup, a lower alkoxy-substituted lower alkyl group, a lower acyl group,a benzyl group, a benzoyl group, or a mono- or di-loweralkoxy-substituted benzoyl group, Z⁴ is a hydrogen atom, a halogen atom,a cyano group, a lower alkoxycarbonyl group, a lower acyloxy group, alower alkoxy group, a lower alkoxy-substituted lower alkoxy group, anamino group, a lower alkoxycarbonylamino group, or a loweralkylsulfonylamino group.

The terms used in the specification are explained below.

The “lower alkyl group” and the “lower alkyl moiety” include a straightchain or branched chain alkyl group having 1 to 6 carbon atoms, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, hexyl, etc.

The “halogeno-lower alkyl group” and the “halogeno-lower alkyl moiety”include a straight chain or branched chain alkyl group having 1 to 6carbon atoms, which is substituted by a halogen atom, for example,trifluoromethyl group.

The “cyclo-lower alkyl group” and the “cyclo-lower alkyl moiety” includea cyclic alkyl group having 3 to 6 carbon atoms, for example,cyclopentyl and cyclohexyl.

The “lower acyl group” and the “lower acyl moiety” include a straightchain or branched chain alkanoyl group having 1 to 5 carbon atoms, forexample, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, andpivaloyl.

The “halogen atom” is fluorine atom, chlorine atom, bromine atom, andiodine atom.

The “lower alkoxy group” and the “lower alkoxy moiety” include astraight chain or branched chain alkoxy group having 1 to 6 carbonatoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, sec-butoxy, tert-butoxy, and hexyloxy.

The “cyclo-lower alkoxy group” and the “cyclo-lower alkoxy moiety”include a cyclic alkoxy group having 3 to 6 carbon atoms, for example,cyclopentyloxy and cyclohexyloxy.

The “lower alkenyl group” and the “lower alkenyl moiety” include astraight chain or branched chain alkenyl group having 2 to 6 carbonatoms, for example, allyl, 2-butenyl, and 3-methyl-2-butenyl.

Among the present compounds (I) of the present invention, preferable oneis a compound of the formula (I) wherein A is an oxygen atom, a sulfuratom, CH₂ or NH, Z¹ and Z² are the same or different and each a hydrogenatom, a halogen atom, a hydroxy group, a lower alkoxy group, acyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, ahalogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxygroup, a carboxyl-substituted lower alkoxy group, a loweralkoxycarbonyl-substituted lower alkoxy group, a mono- or di-loweralkylaminocarbonyl group, a lower acyloxy group, an amino group, a mono-or di-lower alkylamino group, a lower acylamino group, a loweralkoxycarbonylamino group, a lower alkylsulfonylamino group, a carbamoylgroup, or a group which can be converted into a hydroxy group in vivo,or a pharmaceutically acceptable salt thereof.

More preferable compounds are compounds of the formula (Ia) or apharmaceutically acceptable salt thereof.

wherein

A¹ is an oxygen atom, a sulfur atom, CH₂ or NH;

X¹¹ is a hydrogen atom, a halogen atom, a nitro group, a cyano group, ahydroxy group, a lower alkyl group, a hydroxy-substituted lower alkylgroup, a halogeno-lower alkyl group, a lower alkoxy group, ahydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, alower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonylgroup, or a lower acyl group;

X²¹ is a hydrogen atom, a halogen atom, a lower alkyl group, a loweralkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-loweralkoxy group;

Y¹ is a hydrogen atom or a lower alkyl group;

Z¹¹ and Z²¹ are the same or different and each a hydrogen atom, ahalogen atom, a hydroxy group, a lower alkoxy group, a cyclo-loweralkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-loweralkoxy group, a lower alkoxy-substituted lower alkoxy group, acarboxy-substituted lower alkoxy group, a loweralkoxycarbonyl-substituted lower alkoxy group, a mono- or di-loweralkylaminocarbonyl group, a lower acyloxy group, an amino group, a mono-or di-lower alkylamino group, a lower acylamino group, a loweralkoxycarbonylamino group, a lower alkylsulfonylamino group, a carbamoylgroup, or a group which can be converted into a hydroxy group in vivo.

Especially preferable compounds are the following compounds or apharmaceutically acceptable salt thereof.

2-phenoxy-3-[3-(pyridin-4-yl)propoxy]pyridine;

2-(3-bromophenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine;

2-(3-fluorophenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine;

2-(3-fluorophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine;

2-(3-chlorophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine;

2-(3-bromophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine;

2-(3-chlorophenoxy)-3-[3-(3-aminopyridin-4-yl)propoxy]pyridine;

2-phenoxy-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine;

2-phenoxy-3-[3-(3-acetoxypyridin-4-yl)propoxy]pyridine;

2-(3-chlorophenoxy)-3-[3-(3-acetoxypyridin-4-yl)propoxy]pyridine;

2-(3-chlorophenoxy)-3-[3-(3-chloro-5-hydroxypyridin-4-yl)propoxy]pyridine;

2-(3-chlorophenoxy)-3-[3-(3-hydroxypyridin-5-yl)propoxy]pyridine;

2-(3-chlorophenoxy)-3-[3-(3-amino-5-hydroxypyridin-4-yl)propoxy]pyridine;

2-(3-chlorophenoxy)-3-[3-(3-methylsulfonylaminopyridin-4-yl)propoxy]pyridine;and

2-(3-bromophenylthio)-3-[3-(pyridin-4-yl)propoxy]pyridine.

The representative compounds (I) of the present invention are thecompounds as listed in the following Table 1 or a pharmaceuticallyacceptable salt thereof, in addition to the compounds of Examples asdisclosed hereinbelow.

TABLE 1

Attach- ing A n Position X¹ X² Y¹ Z¹ Z² CH₂ 3 4 3-Br H H H H O 3 43-CONH₂ H H H H O 3 4 3-CH₂OH H H H H O 3 4 3- H H H H CONMe₂ O 3 43-NH₂ H H H H O 3 4 3-NHAc H H H H O 3 3 H H H 2-OH H O 3 3 H H H 6-OH HNH 3 4 H H H H H O 3 4 3-Br H H 3-OH 2- CH₂OH S 3 4 3-Cl H H 3-OH H O 34 3-Cl 2- H 3-OH H OMe O 3 4 3-Cl H H 3-OCONMe₂ H O 3 4 3-Br H H 3-OAc HO 3 4 3-Cl H H 3-pivaloyloxy H O 3 4 3-OCF₃ H H 3-OH H O 3 4 3-Cl H H3-CH₂OH H O 3 4 3-Cl H H 3-NHAc H O 3 4 3-Cl H H 3-CONH₂ H O 3 4 3-Cl H6-Me 3-OH H O 3 4 3-Cl H 4-Me 3-OH H O 3 4 3-Cl H H 2-OH H O 2 4 3-Cl HH 3-OH H O 3 4 3-Cl H H 3-(5-tetrazolyl) H Note Attaching position meansthe position at which the alkylene group is bonded to the pyridine ring.In Table 1, the following abbreviations are used in order to simplifythe description. Me: methyl group, Ac: acetyl group.

The compounds (I) of the present invention may be prepared, for example,by the following processes (a) and (b), as explained below.

Process (a)

The compound of the formula (I) wherein A is an oxygen atom, a sulfuratom or CHR¹ may be prepared, if necessary, by protecting by aconventional method a compound of the formula (III):

wherein A² is an oxygen atom, a sulfur atom or CHR¹, X¹² and X²² are thesame or different and each a hydrogen atom, a halogen atom, a nitrogroup, a cyano group, a lower alkyl group, a halogeno-lower alkyl group,a lower alkoxy group, a cyclo-lower alkoxy group, a halogeno-loweralkoxy group, a lower alkoxy-substituted lower alkoxy group, a loweralkoxycarbonyl group, a lower acyl group or a lower acyloxy group, andR¹ and Y¹ are as defined above,

and a compound of the formula (IV):

wherein Z¹² and Z²² are the same or different and each a hydrogen atom,a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, alower alkoxy group, a cyclo-lower alkoxy group, a loweralkoxy-substituted lower alkoxy group, a lower alkoxycarbonyl group, alower acyloxy group, a benzyloxy group, a benzoyloxy group, a mono- ordi-lower alkoxy-substituted benzoyl group, a mono- or di-loweralkoxy-substituted benzoyloxy group, an amino group, a loweralkoxycarbonylamino group or a lower alkylsulfonylamino group, and n isas defined above,

followed by condensing these compounds in the presence of atriphenylphosphine and a dialkyl azodicarboxylate in a suitable solvent,then, if necessary, by removing the protecting groups from theresultant, and further converting the substituents X¹², X²², Z¹², Z²² toother substituents by a conventional method, if required.

The dialkyl azodicarboxylate includes, for example, dimethylazodicarboxylate, diethyl azodicarboxylate, diisopropylazodicarboxylate, dibenzyl azodicarboxylate, etc. In addition, atrialkylphosphine such as tri-n-butylphosphine, etc. may be used insteadof triphenylphosphine. The reaction is preferably carried out at atemperature of from −50° C. to 120° C., more preferably at a temperatureof from 0° C. to 80° C. The solvent may be tetrahydrofuran, toluene,xylene, dichloromethane, etc.

The compound of the formula (IV) may include a compound of the aboveformula (II), i.e., a compound of the (IV) wherein one of Z¹² and Z²² isbonded to the 3-position of the pyridine ring as OZ³, and the other isbonded to the 4- or 5-position of the pyridine ring as Z⁴, and ahydroxyalkylene group wherein n is 3 is bonded to the 4- or 5-positionof the pyridine ring to which the above Z⁴ is not bonded.

Process (b)

The compound of the formula (I) wherein A is an oxygen atom, a sulfuratom or NR² may be prepared by reacting a compound of the formula (V):

wherein L is a halogen atom or a nitro group, Z¹³ and Z²³ are the sameor different and each a hydrogen atom, a halogen atom, a cyano group, alower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, alower alkoxy-substituted lower alkoxy group, or a lower alkoxycarbonylgroup, and Y¹ and n are as defined above,

with a compound of the formula (VI):

wherein A³ is an oxygen atom, a sulfur atom or NR², and R², X¹² and X²²are as defined above,

in the presence of a base and a copper catalyst in a suitable solvent,and if necessary, by removing the protecting groups from the resultingcompound, and then further followed by converting the substituents X¹²,X²², Z¹³, Z²³ to other substituents by a conventional method, ifrequired. The base is preferably an alkali metal hydride, an alkalimetal carbonate, etc. The copper catalyst may preferably be cuprousiodide, cuprous bromide, cuprous chloride, copper powder, cuprous oxide,cupric bromide, etc. The reaction is carried out at a temperature offrom 80° C. to 220° C., preferably at a temperature of from 100° C. to180° C. The solvent may preferably be dimethylformamide,dimethylimidazolidinone, dimethylsulfoxide, dimethylacetamide, pyridine,toluene, xylene, etc.

Processes for preparing the starting compounds for Processes (a) and(b), i.e., the compounds of the formulae (II) to (VI), are explainedbelow.

Process for Preparing the Compound of the Formula (III)

The compound of the formula (III) which is a starting compound forProcess (a) wherein A is an oxygen atom, i.e., the compound of theformula (1-4), may be prepared according to the following Scheme 1.Namely, a compound of the formula (1-1) and a compound of the formula(1-2) are reacted in the presence of a base and a copper catalyst in asuitable solvent, and the resulting compound of the formula (1-3) isdeprotected to give a compound of the formula (1-4).

wherein Q is a lower alkyl group, a cyclo-lower alkyl group, a loweralkoxy-substituted lower alkyl group, a lower alkenyl group, a benzylgroup, or a tetrahydropyranyl group, and L, X¹², X²² and Y¹ are asdefined above.

The compound of the formula (1-1) or (1-2) may be commercially availableones or may be prepared by a conventional method. The base may be analkali metal hydride, an alkali metal carbonate, etc. The coppercatalyst may preferably be cuprous iodide, cuprous bromide, cuprouschloride, copper powder, cuprous oxide, cupric bromide, etc. Thereaction is carried out at a temperature of from 80° C. to 220° C.,preferably at a temperature of from 100° C. to 180° C. The solvent maybe dimethylformamide, dimethylimidazolidinone, dimethylsulfoxide,dimethylacetamide, pyridine, toluene, xylene, etc.

The starting compound for Process (a), a compound of the formula (III)wherein A is a sulfur atom, i.e., a compound of the formula (2-3) may beprepared according to the following Scheme 2. Namely, a compound of theformula (2-1) and a compound of the formula (2-2) are reacted in asuitable solvent to give a compound of the formula (2-3).

wherein L, X¹², X²² and Y¹ are as defined above.

The compound of the formula (2-1) or (2-2) may be commercially availableones or may be prepared by a conventional method. The reaction iscarried out at a temperature of from 0° C. to 200° C., preferably at atemperature of from 50° C. to 130° C. The solvent may bedimethylformamide, dimethylimidazolidinone, dimethylsulfoxide,dimethylacetamide, toluene, xylene, tetrahydrofuran, etc.

The starting compound for Process (a), a compound of the formula (III)wherein A is CHR¹, i.e., a compound of the formula (3-6) or (3-8) may beprepared according to the following Scheme 3. Namely, a compound of theformula (3-1) is converted to a lithium salt compound of the formula(3-1a), which is further reacted with a compound of the formula (3-2) togive a compound of the formula (3-3). When R¹ is a hydrogen atom, acompound of the formula (3-3) is oxidized to give a compound of theformula (3-4), which is further subjected to reduction to give acompound of the formula (3-5). The compound (3-5) is further deprotectedto give a compound of the formula (3-6). When R¹ is a lower alkyl group,the compound (3-3) is subjected to reduction to give a compound of theformula (3-7), which is further deprotected to give a compound of theformula (3-8).

wherein L¹ is a bromine atom or a iodine atom, and R¹, Q, X¹², X²² andY¹ are as defined above.

The compound of the formula (3-1) or (3-2) may be commercially availableones or may be prepared by a conventional method. The compound of theformula (3-1) can be converted to a corresponding lithium salt thereofby reacting with a base such as n-butyl lithium in a suitable solvent.The reaction is preferably carried out at a temperature of from −150° C.to 100° C., preferably at a temperature of from −80° C. to 0° C. Thesolvent may be toluene, xylene, tetrahydrofuran, diethyl ether, dioxane,etc.

A compound of the formula (3-2) is added to a reaction solutioncontaining the compound of the formula (3-1a) thus obtained and reacted.The reaction is carried out at a temperature of from −150° C. to 100°C., preferably at a temperature of −80° C. to 0° C.

The compound of the formula (3-4) is obtained by reacting a compound ofthe formula (3-3) wherein R¹ is a hydrogen atom in the presence of anoxidizing agent such as activated manganese dioxide, etc. in a suitablesolvent. The reaction is carried out at a temperature of from −20° C. to120° C., preferably at a temperature of from 0° C. to 100° C. Thesolvent may be toluene, tetrahydrofuran, dioxane, methylene chloride,hexane, etc.

The reduction of the compound of the formula (3-4) is carried out in thepresence of hydrazine and a base in a suitable solvent. The base may bean alkali metal hydroxide such as sodium hydroxide, potassium hydroxide,etc., and the solvent may be ethylene glycol, diethylene glycol, etc.The reaction is carried out at a temperature of from 0° C. to 220° C.,preferably at a temperature of from 100° C. to 200° C.

The compound of the formula (3-7) is obtained by subjecting a compoundof the formula (3-3) wherein R¹ is a lower alkyl group to catalyticreduction in the presence of palladium carbon, and if necessary, in thepresence of an acid catalyst such as hydrochloric acid, acetic acid,perchloric acid, etc. in a suitable solvent under hydrogen atmosphere.The reaction is carried out at a temperature of from −40° C. to 110° C.,preferably at a temperature of from 0° C. to 70° C. The solvent may bemethanol, ethanol, ethyl acetate, toluene, xylene, tetrahydrofuran,dioxane, etc.

The removal of a protecting group from the compound (3-5) and thecompound (3-7) is carried out in the presence of a suitable acid such ashydrochloric acid, hydrobromic acid, sulfuric acid, camphor-sulfonicacid, etc. in a suitable solvent such as water, methanol, ethanol,isopropanol, acetic acid, etc. The reaction is carried out at atemperature of from −50° C. to 100° C., preferably at a temperature offrom 20° C. to 70° C.

Process for Preparing a Compound of the Formula (II) or the Formula (IV)

The starting compound for Process (a), i.e. the compound of the formula(IV) may be commercially available one or may be prepared according tothe following Scheme 4. Besides, the compound of the formula (II) whichis within the scope of the compound of the formula (IV), i.e., thecompound of the formula (IV) wherein one of Z¹² and Z²² is bonded to the3-position of the pyridine ring as OZ³, and the other is bonded to the4- or 5-position of the pyridine ring as Z⁴, and a hydroxyalkylene groupwherein n is 3 is bonded to the 4- or 5-position of the pyridine ring towhich said Z⁴ is not bonded may be prepared similarly.

wherein E is a bromine atom or a iodine atom, G is a lower alkyl group,a lower alkoxy-substituted lower alkyl group, an allyl group, a benzylgroup or a tetrahydropyranyl group, Z¹⁴, Z²⁴ are a halogen atom, Z¹⁵,Z²⁵ are the same or different and each a halogen atom, a cyano group, alower alkoxy group, a cyclo-lower alkoxy group, a lower alkoxycarbonylgroup, or a benzyloxy group, and Z¹³, Z²³ and Q are as defined above.

Among the starting compounds (IV) for Process (a), the compound of theformula (IV) wherein n is 2 or 4 is obtained by reacting a compound ofthe formula (4-1) with trimethylsilylmethyl magnesium chloride in asuitable solvent, converting the resulting product into a compound ofthe formula (4-2) by placing it under acidic conditions, further bysubjecting the compound (4-2) to hydroboronation reaction, and tosubsequently oxidation and hydrolysis to give a compound of the formula(4-3), and if necessary, followed by converting Z¹³ and Z²³ by aconventional method.

The compound of the formula (4-1) may be commercially available one ormay be prepared by a conventional method. The reaction of the compound(4-1) with trimethylsilylmethyl magnesium chloride is preferably carriedout at a temperature of from −150° C. to 100° C., preferably at atemperature of from −70° C. to 0° C. The solvent may be toluene, xylene,tetrahydrofuran, diethyl ether, dioxane, etc.

The compound (4-2) thus obtained is subjected to hydroboronation in thepresence of a hydroboronating agent such as a complex ofborane-pyridine, a complex of borane-tetrahydrofuran, or6-borabicyclo[3.3.1]nonane, etc. in a suitable solvent, and then furthersubjected to oxidation and a subsequent hydrolysis under basicconditions. The hydroboronation reaction is carried out at a temperatureof from −150° C. to 100° C., preferably at a temperature of from −70° C.to 50° C. The solvent may be tetrahydrofuran, diethyl ether, dioxane,etc. The oxidation reaction and the subsequent hydrolysis are carriedout by adding an aqueous solution of an alkali metal hydroxide such assodium hydroxide, potassium hydroxide, etc. to the reaction solution ofhydroboronation, and then by using an aqueous hydrogen peroxidesolution. The reaction is carried out at a temperature of from −100° C.to 100° C., preferably at a temperature of from −70° C. to 50° C.

Among the starting compounds (IV) for Process (a), the compound of theformula (IV) wherein n is 3 is prepared by reacting a compound (4-4)with an alkali metal salt of a trialkylphosphonoacetate in a suitablesolvent to give the compound (4-5), which is further subjected tocatalytic hydrogenation, and further subjecting the resulting compound(4-6) to hydride reduction to give the compound (4-7), and if necessary,followed by converting Z¹³, Z²³ by a conventional method.

The compound (4-4) may be commercially available one or may be preparedby a conventional method. The reaction of the compound (4-4) is carriedout by reacting an alkali metal salt of a trialkylphosphonoacetate,which is obtained by reacting a trialkylphosphonoacetate such astrimethylphosphonoacetate, triethylphosphonoacetate, etc. with an alkalimetal hydride such as sodium hydride, potassium hydride, etc. in asuitable solvent. The reaction is carried out at a temperature of from−50° C. to 100° C., preferably at a temperature of from −20° C. to 70°C. The solvent may be toluene, xylene, tetrahydrofuran, diethyl ether,dioxane, etc.

The compound (4-5) thus obtained may be converted into a compound of theformula (4-6) by catalytic reduction in the presence of a palladiumcarbon under hydrogen atmosphere. The reaction is carried out at atemperature of from −40° C. to 110° C., preferably at a temperature offrom 0° C. to 70° C. The solvent may be methanol, ethanol, ethylacetate, toluene, xylene, tetrahydrofuran, dioxane, etc.

Further, the compound (4-6) is subjected to reduction by using a reagentsuch as lithium aluminum hydride, diisobutyl aluminum hydride, etc., ina suitable solvent. The reaction is carried out at a temperature of from−50° C. to 100° C., preferably at a temperature of from 0° C. to 70° C.The solvent may be toluene, xylene, diethyl ether, tetrahydrofuran,dioxane, etc.

Among the starting compounds (IV) for Process (a), the compound of theformula (IV) wherein n is 3 may also be prepared by reacting a compoundof the formula (4-8) with ethylene oxide in the presence of a base togive a compound of the formula (4-7), and if necessary, followed byconverting Z¹³ and Z²³ by a conventional method.

The compound (4-8) may be commercially available one or may be preparedby a conventional method. The compound (4-8) may be converted into acompound of the formula (4-7) by treating with a base such as lithiumdiisopropylamide, lithium hexamethyldisilazide, sodium amide, etc. in asuitable solvent to give a corresponding alkali metal salt thereof,followed by reacting with ethylene oxide. The reaction is carried out ata temperature of from −120° C. to 100° C., preferably at a temperatureof from −80° C. to 20° C. The solvent may be toluene, xylene, diethylether, tetrahydrofuran, dioxane, etc.

Among the starting compounds (IV) for Process (a), the compound of theformula (IV) wherein n is 3 and the 4-position of the pyridine ring is apropanol group may be prepared by reacting a compound of the formula(4-9) with a compound of the formula (4-10) in the presence of a base,if necessary, converting Z¹⁴ of the resulting compound of the formula(4-11) by a conventional method, and removing a protecting group to givea compound of the formula (4-12), if necessary, followed by convertingZ¹⁵ and Z²⁵ by a conventional method.

The compound (4-9) and the compound (4-10) may be commercially availableones or may be prepared by a conventional method. The compound of theformula (4-11) may be prepared by treating the compound of the formula(4-9) with a base such as lithium diisopropylamide, lithiumhexamethyldisilazide, sodium amide, etc. in a suitable solvent to givean alkali metal salt thereof, and further reacting with the compound ofthe formula (4-10). The reaction is carried out at a temperature of from−120° C. to 100° C., preferably at a temperature of from −80° C. to 20°C. The solvent may be toluene, xylene, diethyl ether, tetrahydrofuran,dioxane, etc.

Process for Preparing a Compound of the Formula (V)

The starting compound (V) for Process (b), which is the same compound asa compound of the formula (5-3), may be prepared according to thefollowing Scheme 5. Namely, a compound of the formula (5-1) and acompound of the formula (5-2) are reacted in the presence of atriphenylphosphine and a dialkyl azodicarboxylate in a suitable solventto give a compound of the formula (5-3).

wherein L, Y¹, Z¹³, Z²³ and n are as defined above.

The compound (5-1) may be commercially available one or may be preparedby a conventional method. The dialkyl azodicarboxylate includes dimethylazodicarboxylate, diethyl azodicarboxylate, diisopropylazodicarboxylate, dibenzyl azodicarboxylate, etc. A trialkylphosphinesuch as tri-n-butylphosphine, etc., may be used instead of atriphenylphosphine. The reaction is carried out at a temperature of from−50° C. to 120° C., preferably at a temperature of from 0° C. to 80° C.The solvent may be tetrahydrofuran, toluene, xylene, dichloromethane,etc.

The compound (5-2) may be commercially available one or may be preparedaccording to the reaction scheme as shown in Scheme 4, in a similarmanner as the preparation of the compound of the formula (4-3), thecompound (4-7) and the compound (4-12) as mentioned above.

Process for Preparing a Compound of the Formula (VI)

The starting compound (VI) for Process (b) may be commercially availableone or may be prepared by a conventional method.

Pharmacological Experiments

The pharmacological experiments were done on the representativecompounds of the present compounds. The results and the pharmacologicalactivities of the present compounds are explained as follows.

Experiment 1: PDE IV Inhibitory Activity Test

The PDE IV inhibitory activity test was carried out according to amethod using eosinophils prepared from the abdomen of guinea pig(Souness, J. E. et al., Biochem. Pharmacol. vol. 42, p. 937 (1991)).That is, a homogenizing buffer (10 ml, components: 20 mM Tris-HCl buffer(pH 7.5); 2 mM magnesium chloride; 1 mM dithiothreitol, 5 mMethylenediamine tetraacetate disodium; 250 mM sucrose; 20 μMp-tosyl-l-lysine-chloromethylketone; 10 μg/ml Leupeptine) was added to5×10⁷ cells, and the mixture was centrifuged. To the residue was added asolubilizing buffer (10 ml, sodium deoxycholate (final concentration:0.5%) and sodium chloride (final concentration: 100 mM) were added tothe above homogenizing buffer), and the mixture was centrifuged again.The supernatant was subjected to ultrafiltration using Molcut-II(manufactured by Japan Millipore Limited), and the fraction on themembrane was collected by adding a homogenizing buffer (10 ml) to givean enzyme preparation. Inhibitory activity against the enzyme wasdetermined by comparing the hydrolysis rates of a substrate, cAMP(manufactured by Nacalai Tesque Inc.), by the above enzyme fractionbetween in the test compound-treated group and the vehicle group. Inaddition, a 50% inhibitory concentration, i.e., IC₅₀, was obtained froma concentration-activity curve of a test compound. The compounds ofExamples of the present invention as listed in Table 2 were used as atest compound, and Rolipram RP-73401 and SB-207499, which are known toexhibit a PDE IV inhibitory activity, were used as a control compound.The results are shown in Table 2.

TABLE 2 PDE IV Inhibitory Activity Example 50% Inhibitory No.Concentration (nM) 3 35.6 7. 33.7 14 15.3 15 9.7 30 11 31 15.7 32 14.235 25.8 37 26.8 39 20.5 40 18.3 41 38.6 44 34.6 53 23.4 54 63.3 56 5.657 22.9 65 85.6 69 41.2 70 150 73 200 Rolipram 28.4 RP-73401 0.18SB-207499 11

As is clear from Table 2, the present compounds of the formula (I)exhibit a potent inhibitory activity against PDE IV isolated andpurified from guinea pig eosinophils.

Experiment 2: Inhibitory Effect on Antigen-induced Bronchoconstriction

Hartley male guinea pigs were actively sensitized by intraperitoneallyadministering an ovalbumin (manufacture by Sigma). Four weeksthereafter, the animals were anesthetized with Nembutal (50 mg/kg, i.p.,manufactured by Dainabot Co., Ltd.), and a cannula was inserted at theairway, and the bronchoconstriction response of the animals underartificial respiration was observed. The response of the airway wasmeasured by Konzett-Roessler method (Naunyn-Schmiedebergs, Arch. Exp.Pathol. Pharmacol., vol. 195, p. 71 (1940)). A test compound (thecompounds of Examples of the present invention as listed in Table 3) wasorally administered to the animals one hour prior to the administrationof the antigen (i.e., ovalbumin, 0.05%/physiological saline solution,i.v.). Only the compound of Example 31 was orally administered 2 hoursprior to the administration of the antigen. The inhibitory rate (%)caused by the test compound was calculated by comparing thebronchoconstriction response of the test compound-treated group withthat of the control group to which only a solvent was administered. Theresults are shown in Table 3.

TABLE 3 Inhibitory effect on antigen-induced bronchoconstriction ExampleNo. Dose (mg/kg) Inhibitory Rate (%)  3 10 59.9  7 10 77.2 26 10 48.3 2810 54 29 10 42 30 10 46.5 31  3 39 31 10 66 31 30 69 32  3 34 32 10 7032 30 72 35 10 49.3 37 10 49.6 39 10 66.3 40 10 45.3 44 10 55 46 10 45.754 10 33

As is shown in Table 3, the present compounds of the formula (I)exhibited a potent inhibitory activity against the bronchoconstrictionof guinea pig induced by the antigen.

As is clear from the above Pharmacological Experiments, the compounds(I) of the present invention show a potent PDE IV inhibitory activity aswell as an excellent bronchodilating activity.

Besides, the present compounds (I) of the present invention are lowtoxic. In an acute toxicity test, for example, the compound of Example31 never showed any toxicity even at a dose of 2000 mg/kg.

The compounds (I) of the present invention can be administered as a PDEIV inhibitor either orally, parenterally or rectally. The compounds ofthe present invention can also be administered by transpulmonaryinfiltration, oral mucous administration, trans-nasal mucousadministration. The dose of the compounds of the present inventionvaries according to the administration routes, the conditions, ages ofthe patients, etc., or by the object of the administration, i.e.,prophylaxis or treatment, but it is usually in the range of 0.01-100mg/kg/day, preferably in the range of 0.1-50 mg/kg/day.

The compounds (I) of the present invention are usually administered inthe form of a pharmaceutical preparation, which is prepared by mixingthereof with a pharmaceutically acceptable carrier or diluent. Thepharmaceutically acceptable carrier or diluent may be any conventionalones being usually used in the pharmaceutical field, and do not reactwith the compounds (I) of the present invention. Suitable examples ofthe pharmaceutically acceptable carrier or diluent are, for example,lactose, glucose, mannitol, dextrin, starch, white sugar, magnesiummetasilicate aluminate, synthetic aluminum silicate, crystallinecellulose, sodium carboxymethylcellulose, hydroxypropyl starch, calciumcarboxylmethylcellulose, ion exchange resin, methylcellulose, gelatin,gum arabic, hydroxypropyl cellulose, low substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinylalcohol, light anhydrous silicic acid, magnesium stearate, talc,carboxyvinyl polymer, titanium oxide, sorbitan fatty acid ester, sodiumlaurylsulfate, glycerin, glycerin fatty acid ester, purified lanolin,glycerogelatin, polysorbate, macrogol, vegetable oil, wax, nonionicsurfactant, propyleneglycol, water, etc.

The pharmaceutical preparation is, for example, tablets, capsules,granules, powders, syrups, suspensions, suppositories, gels, injectionpreparations, inhalants, nasal drops, etc. These preparations may beprepared by a conventional method. In the preparation of liquids, thecompound of the present invention may be dissolved or suspended in wateror a suitable other solvent, when administered. Tablets and granules maybe coated by a conventional method. In the injection preparations, it ispreferable to dissolve the compound (I) in water, but if necessary, byusing an isotonic agent, and further, a pH adjuster, a buffering agentor a preservative may be added thereto.

These preparations may contain the compound (I) of the present inventionat a ratio of at least 0.01%, preferably at a ratio of 0.05-70%. Thesepreparations may also contain other therapeutically effective compoundsas well.

In addition, these preparations may be used together with anantiallergic agent, a steroid, a β₂-stimulant, an anticholinergic agent,if necessary.

Best Mode for Carrying Out the Invention EXAMPLES

The present invention is illustrated in more detail by the followingExamples, but should not be construed to be limited thereto. Theidentification of the compounds is carried out by Elemental analysis,hydrogen nuclear magnetic resonance spectrum (¹H-NMR), etc.

The following abbreviations are used in the description of ¹H-NMR inorder to simplify the description.

J: coupling constant

s: singlet

d: doublet

dd: double doublet

ddd: double double doublet

t: triplet

dt: double triplet

q: quartet

m: multiplet

In Reference Examples and Examples, basic silica gel columnchromatography was carried out using Chromatorex NH manufactured by FujiSilysia Chemical Ltd.

Reference Example 1 Preparation of 2-(3-bromophenylthio)-3-pyridinol

2-Bromo3-pyridinol (44 g, 250 mmol) and 3-bromothiophenol (30 g, 160mmol) are dissolved in tetrahydrofuran (hereinafter, occasionallyreferred to as THF) (100 ml) and dimethylformaldehyde (hereinafter,referred to as DMF) (100 ml), and the mixture is heated under reflux for5 hours. After being allowed to cool, ethyl acetate (1000 ml) is addedto the mixture, and the mixture is washed with 5% aqueous sodiumhydroxide solution (50 ml×2) and a saturated brine (100 ml×2), and driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue is recrystallized from ethyl acetate to give thetitle compound (35 g) as colorless crystals, m.p. 125-126° C.

The corresponding starting compounds are reacted in a similar manner asin Reference Example 1 to give the compounds of Reference Examples 2 to8.

Reference Example 2 2-(2-bromophenylthio)-3-pyridinol

M.p. 191-192° C.

Reference Example 3 2-(4-bromophenylthio)-3-pyridinol

M.p. 214-216° C.

Reference Example 4 2-(3-trifluoromethylphenylthio)-3-pyridinol

M.p. 125-126° C.

Reference Example 5 2-(3-fluorophenylthio)-3-pyridinol

M.p. 147-148° C.

Reference Example 6 2-(3-chlorophenylthio)-3-pyridinol

M.p. 148-149° C.

Reference Example 7 2-(3-methoxyphenylthio)-3-pyridinol

M.p. 116-117° C.

Reference Example 8 2-phenylthio3-pyridinol

M.p. 137-138° C.

Reference Example 9 Preparation of 2-(3-hydroxyphenylthio)-3-pyridinol

A mixture of 2-(3-methoxyphenylthio)-3-pyridinol (2.0 g, 8.6 mmol)obtained in Reference Example 7 and pyridine hydrochloride (17 g) isstirred at 200° C. for one hour. After being allowed to cool, themixture is neutralized with a saturated aqueous sodium hydrogencarbonate solution, and extracted with ethyl acetate (300 ml). Theorganic layer is washed with a saturated brine (100 ml×2), dried overanhydrous magnesium sulfate, and concentrated to dryness under reducedpressure. The residue is purified by silica gel column chromatography(eluent: ethyl acetate), and further recrystallized from diethyl etherto give the title compound (1.24 g) as colorless crystals, m.p. 147-148°C.

Reference Example 10 Preparation of 2-bromo-3-cyclopentyloxypyridine

Triphenylphosphine (94 g, 360 mmol) and cyclopentanol (43 g, 500 mmol)are dissolved in THF (500 ml), and thereto are added with stirringdiisopropyl azodicarboxylate (71 g, 350 mmol) at room temperature. Tothe mixture is added 2-bromo-3-pyridinol (50 g, 290 mmol) underice-cooling, and the mixture is stirred at room temperature for 30minutes. The reaction solution is concentrated under reduced pressure,and the residue is purified by silica gel column chromatography (eluent:ethyl acetate/hexane) to give the title compound (51 g) as a pale yellowoil.

Reference Example 11 Preparation of 2-(3-bromophenoxy)-3-pyridinol

(i) 2-Bromo-3-cyclopentyloxypyridine (20 g, 83 mmol) obtained inReference Example 10 and 3-bromophenol (26 g, 150 mmol) are dissolved inDMF (50 ml), and thereto are added potassium carbonate (42 g, 300 mmol)and cuprous bromide (18 g, 130 mmol), and the mixture is stirred at 140°C. for one hour. After being allowed to cool, the reaction solution ispoured into ice, and thereto is added a 48% hydrobromic acid (50 ml),and the mixture is stirred for 15 minutes. To the mixture is addedpotassium carbonate (200 g), and the pH value of the mixture is adjustedto pH 12. The mixture is extracted with ethyl acetate (500 ml×2). Theorganic layer is washed with a saturated brine (100 ml×2), dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue is purified by basic silica gel column chromatography(eluent: ethyl acetate/hexane) to give2-(3-bromophenoxy)-3-cyclopentyloxypyridine as a pale yellow oil.

(ii) The oily product obtained in the above is dissolved in acetic acid(250 ml), and thereto is added a 47% aqueous hydrobromic acid solution(100 ml), and the mixture is heated under reflux for 4 hours. Thereaction solution is concentrated under reduced pressure, andneutralized with a saturated aqueous sodium hydrogen carbonate solution,and extracted with ethyl acetate (500 ml×2). The organic layer is washedwith a saturated brine (100 ml×2), dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue ispurified by basic silica gel column chromatography (eluent: ethylacetate/hexane), and further recrystallized from isopropyl ether/hexaneto give the title compound (15 g) as colorless crystals, m.p. 107-108°C.

The corresponding starting compounds are reacted in a similar manner asin Reference Example 11 to give the compounds of Reference Examples 12to 14.

Reference Example 12 2-phenoxy-3-pyridinol

M.p. 92-93° C.

Reference Example 13 2-(3-fluorophenoxy)-3-pyridinol

M.p. 84-85° C.

Reference Example 14 2-(3-chlorophenoxy)-3-pyridinol

M.p. 86-90° C.

Reference Example 15 Preparation of 2-(3-cyanophenoxy)-3-methoxypyridine

2-Bromo-3-methoxypyridine (15 g, 68 mmol) and 3-cyanophenol (8.9 g, 75mmol) are dissolved in DMF (150 ml), and thereto are added potassiumcarbonate (28 g, 0.2 mol) and cuprous bromide (10.7 g, 75 mmol), and themixture is heated under reflux at 140° C. for 1.5 hours. After beingallowed to cool, to the reaction solution is added ethyl acetate (1000ml), and the mixture is washed with a saturated brine (200 ml×2), driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue is recrystallized from isopropyl ether/hexane togive the title compound (11.1 g) as pale brown crystals, m.p. 88-89° C.

Reference Example 16 Preparation of 2-(3-cyanophenoxy)-3-pyridinol

2-(3-Cyanophenoxy)-3-methoxypyridine (10 g, 44 mmol) obtained inReference Example 15 is dissolved in methylene chloride (400 ml), and tothe mixture is added a solution of boron tribromide in methylenechloride (170 ml, 170 mmol) under ice-cooling. The mixture is furtherstirred at room temperature for 36 hours, and the reaction is quenchedby adding thereto a saturated brine. The mixture is neutralized withsodium hydrogen carbonate, and extracted with chloroform (500 ml×2). Theorganic layer is washed with a saturated brine (200 ml×2), dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue is purified by basic silica gel column chromatography(eluent: chloroform/ethanol) to give the title compound (5.2 g) ascolorless crystals, m.p. 130-133° C.

Reference Example 17 Preparation of 2-(3-acetylphenoxy)-3-pyridinol

2-(3-Cyanophenoxy)-3-pyridinol (3.0 g, 14 mmol) obtained in ReferenceExample 16 is dissolved in THF (50 ml), and thereto is added a solutionof methyl lithium in diethyl ether (21.4 ml, 30 mmol) at −70° C., andthe mixture is stirred for 30 minutes. The reaction is quenched byadding thereto acetone (5 ml). The mixture is acidified with a 10%aqueous hydrochloric acid solution (15 ml), and then neutralized withsaturated aqueous sodium hydrogen carbonate solution, and extracted withethyl acetate (300 ml×2). The organic layer is washed with a saturatedbrine (200 ml×2), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue is purified by silicagel column chromatography (eluent: ethyl acetate/hexane) to give thetitle compound (3.0 g) as a pale yellow oil.

Reference Example 18 Preparation of2-(3-ethoxycarbonylphenoxy)-3-pyridinol

(i) 3-Benzyloxy-2-bromopyridine (8 g, 30 mmol) and ethyl3-hydroxybenzoate (13.3 g, 80 mmol) are dissolved in DMF (50 ml), andthereto are added potassium carbonate (28 g, 0.2 mol) and cuprousbromide (11.5 g, 80 mmol). The mixture is heated under reflux at 140° C.for one hour. After being allowed to cool, the reaction solution isacidified with a 15% aqueous hydrochloric acid solution (50 ml), andthen neutralized with a saturated aqueous sodium hydrogen carbonatesolution, and extracted with ethyl acetate (300 ml×2). The organic layeris washed with a saturated brine (200 ml×2), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residueis purified by silica gel column chromatography (eluent: ethylacetate/hexane) to give 3-benzyloxy-2-(3-ethoxycarbonylphenoxy)pyridineas a pale yellow oil.

(ii) The oily product obtained in the above is dissolved in ethanol (100ml), and thereto is added 5% palladium carbon (1.0 g), and the mixtureis stirred at room temperature for one hour under hydrogen atmosphere.The reaction solution is filtered and the insoluble materials areremoved, and the filtrate is concentrated under reduced pressure. Theresidue is purified by basic silica gel column chromatography (eluent:ethyl acetate/ethanol), and further recrystallized from diethylether/hexane to give the title compound (5.4 g) as colorless crystals,m.p. 117-118° C.

Reference Example 19 Preparation of2-(3-bromobenzolyl)-3-methoxymethoxypyridine

2-Bromo-3-methoxymethoxypyridine (22 g, 100 mmol) is dissolved indiethyl ether (500 ml), and thereto is added a solution of n-butyllithium in hexane (69 ml, 110 mmol) under cooling at −60° C., and themixture is stirred for 15 minutes. 3-Bromobenzaldehyde (20 g, 110 mmol)is added to the mixture, and the mixture is stirred for 10 minutes, andthen the reaction is quenched with a saturated brine. The mixture isextracted with ethyl acetate (500 ml×2), and washed with a saturatedbrine (200 ml×2), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue is dissolved inchloroform (100 ml) and hexane (300 ml), and thereto is added activatedmanganese dioxide (200 g). The mixture is stirred at room temperaturefor one hour, and the reaction solution is filtered. The filtrate isconcentrated under reduced pressure, and the residue is purified bysilica gel column chromatography (eluent: ethyl acetate/hexane), andfurther recrystallized from isopropyl ether/hexane to give the titlecompound (25 g) as colorless crystals, m.p. 101-102° C.

Reference Example 20 Preparation of 2-(3-bromobenzyl)-3-pyridinol

2-(3-Bromobenzolyl)-3-methoxymethoxypyridine (6.7 g, 21 mmol) obtainedin Reference Example 19 is dissolved in ethylene glycol (67 ml), andthereto are added hydrazine.monohydrate (3.4 ml) and potassium hydroxide(5.0 g, 76 mmol), and the mixture is stirred at 90° C. for 5 hours.After being allowed to cool, water (200 ml) is added to the mixture, andthe mixture is extracted with ethyl acetate (150 ml×2), washed with asaturated brine (200 ml×2), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue is recrystallized fromisopropyl ether to give the title compound (4.9 g) as pale browncrystals, m.p. 160-162° C.

Reference Example 21 Preparation of3-(3,5-dimethoxypyridin-4-yl)propenoic acid ethyl ester

3,5-Dimethoxypyridine (8.1 g, 58 mmol) is dissolved in THF (100 ml), andthereto is added a solution of n-butyl lithium in hexane (45.3 ml, 70mmol) at −20° C., and the mixture is warmed to 0° C. The mixture isstirred for 30 minutes, and cooled to −78° C. To the mixture is addedDMF (5.4 ml, 70 mmol), and the mixture is warmed to 0° C. over a periodof time for 30 minutes. Then, to the reaction solution is added asolution of a salt which is prepared from triethylphosphonoacetate (15.6g, 69 mmol) and sodium hydride (60% in mineral oil, 2.78 g, 69 mmol) inTHF (50 ml) at 0° C., and the mixture is stirred for one hour. Thereaction solution is poured into ice-water, extracted with ethyl acetate(200 ml×2), washed with a saturated brine (100 ml×2), dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue is purified by silica gel column chromatography (eluent:chloroform/methanol), and further recrystallized from isopropylether/hexane to give the title compound (7.3 g) as colorless crystals,m.p. 100-101° C.

Reference Example 22 Preparation of3-(3,5-dimethoxypyridin-4-yl)propionic acid ethyl ester

3-(3,5-Dimethoxypyridin-4-yl)propenoic acid ethyl ester (6.5 g, 27 mmol)obtained in Reference Example 21 is dissolved in ethanol (200 ml), andthereto is added a 10% palladium carbon (1.0 g), and the mixture isstirred at room temperature under hydrogen atmosphere. After thetheoretical amount of hydrogen gas is consumed, the reaction solution isfiltered, and the filtrate is concentrated under reduced pressure. Theresidue is purified by silica gel column chromatography (eluent: ethylacetate/hexane), and recrystallized from hexane to give the titlecompound (7.1 g) as colorless crystals, m.p. 66-67° C.

Reference Example 23 Preparation of3-(3,5-dichloropyridin-4-yl)-1-propanol

(i) 3,5-Dichloropyridine (4.4 g, 30 mmol) is dissolved in THF (100 ml),and thereto is added a solution of n-butyl lithium in hexane (19 ml, 30mmol) at −70° C., and the mixture is stirred for 15 minutes.1-Bromo-3-methoxymethoxypropane (6.0 g, 33 mmol) is added to themixture, and the mixture is warmed to 0° C. over a period of time forone hour. The reaction is quenched with a saturated brine (50 ml), andthe mixture is extracted with ethyl acetate (150 ml×2). The organiclayer is washed with a saturated brine (100 ml×2), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residueis purified by silica gel column chromatography (eluent: ethylacetate/hexane) to give1-(3,5-dichloropyridin-4-yl)-3-methoxymethoxypropane (1.0 g) as an oil.

(ii) The oily product obtained in the above is dissolved in ethanol (20ml), and thereto is added a 10% sulfuric acid (1 ml), and the mixture isheated under reflux for 30 minutes. The mixture is neutralized with asaturated aqueous sodium hydrogen carbonate solution, extracted withethyl acetate (100 ml), washed with a saturated brine (50 ml×2), driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue is purified by silica gel column chromatography(eluent: ethyl acetate/hexane) to give the title compound (0.70 g) as apale yellow oil.

Reference Example 24 Preparation of3-(3-methoxymethoxypyridin-4-yl)propenoic acid ethyl ester

3-Methoxymethoxypyridine (17.5 g, 130 mmol) is dissolved in THF (500ml), and thereto is added a solution of n-butyl lithium in hexane (88ml, 140 mmol) at −30° C. The mixture is stirred at 0° C. for 20 minutes,and cooled to −70° C. To the mixture is added DMF (11.0 g, 150 mmol),and the mixture is stirred again at 0° C. for 30 minutes. Then, theretois added a solution of a salt which is prepared fromtriethylphosphonoacetate (34.0 g, 150 mmol) and sodium hydride (60% inmineral oil, 6.0 g, 150 mmol) in THF (200 ml) at 0° C., and the mixtureis stirred for one hour. The reaction solution is poured into ice-water,extracted with ethyl acetate (400 ml×2), and the residue is purified bysilica gel column chromatography (eluent: ethyl acetate/hexane) to givethe title compound (22.0 g) as pale yellow oil.

Reference Example 25 Preparation of3-(3-methoxymethoxypyridin-4-yl)propionic acid ethyl ester

3-(3-Methoxymethoxypyridin-4-yl)propenoic acid ethyl ester (22.0 g, 93mmol) obtained in Reference Example 24 is dissolved in ethanol (200 ml),and thereto is added a 5% palladium carbon (2.0 g), and the mixture isstirred at room temperature under hydrogen atmosphere. The theoreticalamount of hydrogen gas is consumed, and the reaction solution isfiltered, and the filtrate is concentrated under reduced pressure. Theresidue is purified by silica gel column chromatography (eluent: ethylacetate/hexane) to give the title compound (21.0 g) as pale yellow oil.

Reference Example 26 Preparation of2-bromo3-[3-(pyridine-3-yl)propoxy]pyridine

3-(Pyridin-3-yl)-1-propanol (12.3 g, 90 mmol) and triphenylphosphine(34.0 g, 130 mmol) are dissolved in THF (200 ml), and thereto are addedsuccessively with stirring diisopropyl azodicarboxylate (22.2 g, 110mmol) and 2-bromo-3-hydroxypyridine (12.0 g, 69 mmol) under ice-cooling.The mixture is stirred at room temperature for 30 minutes, and then thereaction solution is concentrated under reduced pressure. To the residueis added ethyl acetate (300 ml), and the mixture is extracted with a 10%aqueous hydrochloric acid solution (150 ml×2). The pH value of theaqueous layer is adjusted with potassium carbonate to pH 12, and themixture is extracted with ethyl acetate (200 ml×2). The organic layer iswashed with a saturated brine (50 ml×2), dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue ispurified by silica gel column chromatography (eluent: ethylacetate/hexane) to give the title compound (18.3 g) as a colorless oil.

The corresponding starting compounds are reacted in a similar manner asin Reference Example 26 to give the compounds of Reference Examples 27to 29.

Reference Example 27 2-bromo-3-[3-(pyridin-4-yl)propoxy]pyridine

M.p. 78-79° C.

Reference Example 282-chloro-3-[3-(3-methoxymethoxypyridin-4-yl)propoxy]pyridine

Pale brown oil

Reference Example 292-bromo-3-[3-(3-methoxymethoxypyridin-4-yl)propoxy]pyridine

Pale brown oil

Reference Example 30 Preparation of 3-(pyridin-3-yl)-1-butanol

(i) 3-(Pyridin-3-yl)propanal (10 g, 74 mmol) is dissolved in THF (200ml), and thereto is added a solution of trimethylsilylmethyl magnesiumchloride in diethyl ether (100 ml, 100 mmol) under ice-cooling, and themixture is stirred for 15 minutes. The reaction is quenched with asaturated brine (10 ml), and the mixture is extracted with ethyl acetate(300 ml×2), washed with a saturated brine (200 ml×2), dried overanhydrous magnesium sulfate, and concentrated under reduced pressure. Tothe residue are added THF (50 ml) and conc. sulfuric acid (5 ml), andthe mixture is heated under reflux for 20 minutes. After being allowedto cool, the reaction solution is neutralized with a saturated aqueoussodium hydrogen carbonate solution, and extracted with ethyl acetate(200 ml×2). The organic layer is washed with a saturated brine (200ml×2), dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue is purified by silica gel columnchromatography (eluent: ethyl acetate/hexane) to give3-(3-butenyl)pyridine (6.5 g) as a pale yellow oil.

(ii) The oily product obtained in the above is dissolved in THF (100ml), and thereto is added 9-borabicyclo[3.3.1]nonane (14.0 g, 57 mmol)under ice-cooling. The ice bath is removed, and the mixture is furtherstirred at room temperature for 30 minutes, and thereto are carefullyadded again a 30% aqueous sodium hydroxide solution (30 ml), a 30%aqueous hydrogen peroxide solution (25 ml) under ice-cooling. Thereaction solution is extracted with chloroform (500 ml), and the organiclayer is washed with a saturated brine (200 ml×2), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residueis purified by silica gel column chromatography (eluent: ethylacetate/hexane), and further subjected to Kugelrohr distillation to givethe title compound (1.2 g) as a colorless oil.

Reference Example 31 Preparation of 4-(pyridin-4-yl)-1-butanol

3-(Pyridin-4-yl)propanal is treated in a similar manner as in ReferenceExample 30 to give the title compound as a colorless oil.

Reference Example 32 Preparation of 3-(3-bromopyridin-4-yl)-1-propanol

Diisopropylamine (7.1 g, 70 mmol) is dissolved in THF (100 ml), andthereto is added a solution of n-butyl lithium in hexane (35.7 ml, 60mmol) at −70° C., and the mixture is stirred for 15 minutes. Then, tothe mixture is added a solution of 3-bromo-4-methylpyridine (8.6 g, 50mmol) in THF (30 ml). Ten minutes thereafter, to the mixture is addedethylene oxide (2.6 g, 60 mmol), and the mixture is warmed to 0° C. overa period of time for one hour. The reaction is quenched with a saturatedbrine (50 ml), and the mixture is extracted with ethyl acetate (150ml×2). The organic layer is washed with a saturated brine (100 ml×2),dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue is purified by silica gel column chromatography(eluent: ethyl acetate/hexane) to give the title compound (8.5 g) as apale yellow oil.

Reference Example 33 Preparation of 3-cyano-4-methylpyridine

3-Bromo-4-methylpyridine (20.0 g, 116 mmol) is dissolved in DMF (100ml), and thereto is added cuprous cyanide (11.6 g, 30 mmol), and themixture is heated under reflux for 18 hours. After cooling, a 25%aqueous ammonia (200 ml) and a saturated aqueous ammonium chloridesolution (200 ml) are added to the reaction solution, and the mixture isextracted with ethyl acetate (200 ml×5). The organic layer is washedwith a saturated brine (100 ml), dried over anhydrous magnesium sulfate,and concentrated under reduced pressure. The residue is purified bysilica gel column chromatography (eluent: ethyl acetate/hexane) to givethe title compound (11.0 g) as colorless crystals, m.p. 75-78° C.

Reference Example 34 Preparation of 3-(3-cyanopyridin-4-yl)-1-propanol

Diisopropylamine (2.5 g, 25 mmol) is dissolved in THF (30 ml), andthereto is added a solution of n-butyl lithium in hexane (14.3 ml, 24mmol) at −70° C. The mixture is stirred for 15 minutes, and thereto isadded a solution of 3-cyano-4-methylpyridine (2.4 g, 20 mmol) obtainedin Reference Example 33 in THF (20 ml). Ten minutes thereafter, ethyleneoxide (1.1 g, 24 mmol) is added to the mixture, and the mixture iswarmed to 20° C. over a period of time for one hour. The reaction isquenched with a saturated brine (50 ml), and the mixture is extractedwith ethyl acetate (150 ml×2). The organic layer is washed with asaturated brine (100 ml×2), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue is purified by silicagel column chromatography (eluent: ethyl acetate/hexane) to give thetitle compound (1.2 g) as a pale brown oil.

Reference Example 35 Preparation of3-(3-ethoxycarbonylpyridin-4-yl)-1-propanol

3-Cyano-4-pyridine-1-propanol (1.2 g, 7.4 mmol) obtained in ReferenceExample 34 is dissolved in ethanol (35 ml), and thereto is added anaqueous solution (15 ml) of sodium hydroxide (1.2 g, 30 mmol). Themixture is stirred at 45° C. for one hour, and after being allowed tocool, the mixture is neutralized with conc. hydrochloric acid (2.5 ml).The solvent is concentrated under reduced pressure, and the remainingwater is removed by co-distillation with ethanol. Then, the residue isdissolved in a 30% solution of hydrochloric acid in ethanol (100 ml),and the mixture is heated under reflux for 5 hours. The reactionsolution is concentrated under reduced pressure, poured into a saturatedaqueous sodium hydrogen carbonate solution, and extracted with ethylacetate (100 ml×2). The organic layer is washed with a saturated brine(50 ml×2), dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The residue is purified by silica gel columnchromatography (eluent: ethyl acetate/hexane) to give the title compound(1.22 g) as a pale yellow oil.

Reference Example 36 Preparation of 3-(5-benzyloxypyridin-3-yl)propenoicacid ethyl ester

Sodium hydride (60% in mineral oil, 0.71 g, 18 mmol) is suspended in THF(50 ml), and thereto is added triethylphosphonoacetate (3.5 ml, 18mmol), and the mixture is stirred at 0° C. for 20 minutes. To themixture is added 5-benzyloxy-3-pyridylaldehyde (2.50 g, 12 mmol), andthe mixture is further stirred for 45 minutes. The reaction solution ispoured into ice-water (200 ml), and the mixture is extracted with ethylacetate (100 ml×2), washed with a saturated brine (100 ml×2), dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue is purified by silica gel column chromatography (eluent:ethyl acetate/hexane), and further recrystallized from isopropylether/hexane to give the title compound (3.1 g) as pale yellow crystals,m.p. 76-77° C.

Reference Example 37 Preparation of1-(3,5-dichloropyridin-4-yl)-3-(tetrahydropyranyl-2-oxy)propane

Diisopropylamine (10.1 g, 100 mmol) is dissolved in THF (200 ml), andthereto is added with stirring a solution of n-butyl lithium in hexane(57.6 ml, 95 mmol) at −70° C. Ten minutes thereafter, a solution of3,5-dichloropyridine (13.0 g, 88 mmol) in THF (50 ml) is added dropwiseto the mixture over a period of time for 15 minutes during which thebulk temperature should not be raised over −60° C., and then the mixtureis further stirred for 20 minutes. Subsequently,1-bromo-3-(tetrahydropyranyl-2-oxy)propane (20.0 g, 90 mmol) is added tothe mixture, and the mixture is stirred at −70° C. for 2 hours, andcooled to 0° C. over a period of time for 5 hours. The reaction isquenched with a saturated brine (200 ml), and the mixture is extractedwith ethyl acetate (300 ml×2). The extract is washed with a saturatedbrine (100 ml×2), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue is purified by silicagel column chromatography (eluent: ethyl acetate/hexane) to give thetitle compound (8.6 g) as a pale yellow oil.

Reference Example 38 Preparation of1-(3-chloro-5-methoxypyridin-4-yl)-3-(tetrahydropyranyl-2-oxy)propane

1-(3,5-Dichloropyridin-4-yl)-3-(tetrahydropyranyl-2-oxy)propane (8.0 g,28 mmol) obtained in Reference Example 37 is dissolved inN-methylpyrrolidinone (60 ml), and thereto are added a 28% solution ofsodium methylate in methanol (17.4 g, 90 mmol) and cuprous chloride (3.0g, 30 mmol). The mixture is stirred at 110° C. for 3 hours. After beingallowed to cool, to the reaction solution are added a 28% aqueousammonia (30 ml) and water (200 ml), and the mixture is extracted withethyl acetate (300 ml×2). The extract is washed with a saturated brine(100 ml×2), dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The residue is purified by silica gel columnchromatography (eluent: ethyl acetate/hexane) to give the title compound(4.1 g) as a pale yellow oil.

Reference Example 39 Preparation of1-(3,5-dibromopyridin-4-yl)-3-benzyloxypropane

Diisopropylamine (5.1 g, 50 mmol) is dissolved in THF (100 ml), andthereto is added with stirring a solution of n-butyl lithium in hexane(27.3 ml, 45 mmol) at −70° C. Ten minutes thereafter, a solution of3,5-dibromopyridine (10.0 g, 42 mmol) in THF (30 ml) is added dropwiseover a period of time for 20 minutes during which the bulk temperatureshould not be raised over −60° C., and the mixture is further stirredfor 5 minutes. Subsequently, 1-bromo-3-benzyloxypropane (10.0 g, 44mmol) is added to the mixture, and the mixture is stirred at −70° C. for2 hours. The mixture is warmed to 20° C. over a period of time for 2hours. The reaction is quenched with a saturated brine (200 ml), and themixture is extracted with ethyl acetate (300 ml×2). The extract iswashed with a saturated brine (100 ml×2), dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue ispurified by silica gel column chromatography (eluent: ethylacetate/hexane) to give the title compound (9.0 g) as a pale yellow oil.

Reference Example 40 Preparation of1-(3-bromo-5-methoxypyridin-4-yl)-3-benzyloxypropane

1-(3,5-Dibromopyridin-4-yl)-3-benzyloxypropane (6.0 g, 16 mmol) obtainedin Reference Example 39 is dissolved in N-methylpyrrolidinone (40 ml),and thereto are added a 28% solution of sodium methylate in methanol (20ml) and cuprous bromide (2.0 g, 14 mmol). The mixture is stirred at 110°C. for one hour. After being allowed to cool, to the reaction solutionare added a 28% aqueous ammonia (30 ml) and water (200 ml), and themixture is extracted with ethyl acetate (200 ml×2). The extract iswashed with a saturated brine (100 ml×2), dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue ispurified by silica gel column chromatography (eluent: ethylacetate/hexane) to give the title compound (2.7 g) as a colorless oil.

Reference Example 41 Preparation of1-(3-cyano-5-methoxypyridin-4-yl)-3-benzyloxypropane

1-(3-Bromo-5-methoxypyridin-4-yl)-3-benzyloxypropane (2.7 g, 8.0 mmol)obtained in Reference Example 40 is dissolved in N-methylpyrrolidinone(30 ml), and thereto is added cuprous cyanide (0.9 g, 10 mmol), and themixture is stirred at 180° C. for 4 hours. After being allowed to cool,to the reaction solution are added a 28% aqueous ammonia (30 ml) andwater (100 ml), and the mixture is extracted with ethyl acetate (100ml×2). The extract is washed with a saturated brine (50 ml×2), driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue is purified by silica gel column chromatography(eluent: ethyl acetate/hexane) to give the title compound (2.2 g) as apale yellow oil.

Example 1 Preparation of 3-(3,5-dimethoxypyridin-4-yl)-1-propanol

Lithium aluminum hydride (1.1 g, 30 mmol) is suspended in THF (50 ml),and thereto is added with stirring3-(3,5-dimethoxypyridin-4-yl)propionic acid ethyl ester (3.5 g, 15 mmol)obtained in Reference Example 22 at 50° C. over a period of time for 40minutes. The mixture is further heated under reflux for 30 minutes, andthereto are added successively water (1.1 ml), a 15% aqueous sodiumhydroxide solution (1.1 ml) and water (3.3 ml) in order to quench thereaction. The reaction solution is filtered, and the insoluble materialsare removed, and the filtrate is concentrated under reduced pressure.The residue is purified by silica gel column chromatography (eluent:chloroform/methanol), and further recrystallized from isopropylether/hexane to give the title compound (2.9 g) as colorless crystals,m.p. 88-89° C.

Example 2 Preparation of 3-(3-methoxymethoxypyridin-4-yl)-1-propanol

Lithium aluminum hydride (6.0 g, 0.16 mmol) is suspended in THF (500ml), and thereto is added with stirring3-(3-methoxymethoxypyridin-4-yl)propionic acid ethyl ester (21 g, 89mmol) obtained in Reference Example 25 at 50° C. over a period of timefor 30 minutes. The mixture is heated under reflux for 30 minutes, andthereto are added successively water (6 ml), a 15% sodium hydroxide (6ml) and water (18 ml) in order to quench the reaction. The reactionsolution is filtered to remove the insoluble materials, and the filtrateis concentrated under reduced pressure. The residue is purified bysilica gel column chromatography (eluent: ethyl acetate) to give thetitle compound (17.5 g) as a colorless oil.

¹H-NMR (300 MHz, CDCl₃, δ ppm): 1.83-1.93 (m, 2H), 2.75 (t, 2H, J=8 Hz),3.51 (s, 3H), 3.67 (t, 2H, J=6 Hz), 5.25 (s, 2H), 7.10 (d, 1H, J=5 Hz),8.21 (d, 1H, J=5 Hz), 8.40 (s,1H)

Example 3 Preparation of2-(3-bromophenylthio)-3-[3-(pyridin-3-yl)propoxy]pyridine

3-(Pyridin-3-yl)-1-propanol (5.5 g, 40 mmol) and triphenylphosphine(10.5 g, 40 mmol) are dissolved in THF (120 ml), and thereto are addedsuccessively with stirring diisopropyl azodicarboxylate (6.1 g, 30 mmol)and 2-(3-bromophenylthio)-3-pyridinol (5.0 g, 18 mmol) obtained inReference Example 1 under ice-cooling. The mixture is further stirred atroom temperature for 30 minutes, and the reaction solution isconcentrated under reduced pressure. To the residue is added ethylacetate (300 ml), and the mixture is extracted with a 10% aqueoushydrochloric acid solution (150 ml×2). The pH value of the aqueous layeris adjusted to pH 12 with potassium carbonate, and the mixture isextracted with ethyl acetate (200 ml×2). The organic layer is washedwith a saturated brine (50 ml×2), dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue ispurified by silica gel column chromatography (eluent: ethylacetate/hexane), and recrystallized from diethyl ether to give the titlecompound (6.8 g) as colorless crystals, m.p. 75-76° C.

¹H-NMR (200 MHz, CDCl₃, δ ppm): 2.08-2.22 (m, 2H), 2.86 (t, 2H, J=11Hz), 4.02 (t, 2H, J=8 Hz), 6.98-7.08 (m, 2H), 7.19-7.29 (m, 2H), 7.45(dd, 1H, J=1 Hz, 3 Hz), 7.49 (dd, 1H, J=1 Hz, 3 Hz), 7.51-7.58 (m, 1H),7.69 (t, 1H, J=3 Hz), 8.01 (dd, 1H, J=3 Hz, 6 Hz), 8.47 (dd, 1H, J=3 Hz,7 Hz), 8.50 (dd, 1H, J=1 Hz, 3 Hz)

Examples 4 to 17

The corresponding starting compounds are treated in a similar manner asin Example 3 to give the compounds of Examples 4 to 17 as listed inTable 4.

TABLE 4

Attaching Example n Position X¹ M.p. 4 2 3 3-Br Oil 5 2 4 3-Br 96-97° C.6 3 2 3-Br Oil 7 3 4 3-Br 89-90° C. 8 3 4 2-Br Oil 9 3 4 4-Br Oil 10 3 43-CF₃ Oil 11 3 4 3-F 80-81° C. 12 3 3 3-F 138-142° C. (1.5 oxalate) 13 34 3-OH 158-159° C. 14 3 4 3-OMe 84-85° C. 15 3 4 H 41-43° C. 16 4 3 3-Br67-68° C. 17 4 4 3-Br Oil

Example 18 Preparation of2-(3-cyclopentyloxyphenylthio)-3-[3-(pyridin-4-yl)propoxy]pyridine

Cyclopentanol (0.11 g, 1.3 mmol) and triphenylphosphine (0.47 g, 1.8mmol) are dissolved in THF (15 ml), and thereto are successively addedwith stirring diisopropyl azodicarboxylate (0.26 g, 1.3 mmol) and2-(3-hydroxyphenylthio)-3-[3-(pyridin-4-yl)propoxy]pyridine (0.30 g,0.89 mmol) obtained in Example 13. The mixture is further stirred atroom temperature for 30 minutes, and the reaction solution isconcentrated under reduced pressure. The residue is extracted with a 10%aqueous hydrochloric acid solution (30 ml), and the aqueous layer iswashed with chloroform (30 ml×2), and the pH value thereof is adjustedto pH 12 with potassium carbonate. The mixture is extracted with ethylacetate (50 ml×2), and the organic layer is washed with a saturatedbrine (50 ml×2), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue is purified by silicagel column chromatography (eluent: chloroform/methanol) to give thetitle compound (0.26 g) as a colorless oil.

¹H-NMR (200 MHz, CDCl₃, δ ppm): 1.52-1.93 (m, 8H), 2.08-2.22 (m, 2H),2.85 (t, 2H, J=8 Hz), 4.01 (t, 2H, J=6 Hz), 4.68-4.79 (m, 1H), 6.82-6.89(m, 1H), 6.95-7.18 (m, 4H), 7.13-7.18 (m, 2H), 7.26-7.31 (m, 1H), 8.02(dd, 1H, J=2 Hz, 4 Hz), 8.48-8.53 (m, 2H)

Example 19 Preparation of2-(3-bromophenoxy)-3-[3-(3,5-dimethoxypyridin-4-yl)propoxy]pyridine.difumarate

3-(3,5-Dimethoxypyridin-4-yl)-1-propanol (0.60 g, 3.0 mmol) obtained inExample 1 and triphenylphosphine (1.18 g, 4.5 mmol) are dissolved in THF(30 ml), and thereto are successively added with stirring diisopropylazodicarboxylate (0.78 g, 3.9 mmol) and 2-(3-bromophenoxy)-3-pyridinol(1.04 g, 3.9 mmol) obtained in Reference Example 11 under ice-cooling.The mixture is stirred at room temperature for 30 minutes, and thereaction solution is concentrated under reduced pressure. To the residueis added ethyl acetate (50 ml), and the mixture is extracted with a 10%aqueous hydrochloric acid solution (50 ml×2). The pH value of theaqueous layer is adjusted to pH 12 with potassium carbonate, and themixture is extracted with ethyl acetate (100 ml×2). The organic layer iswashed with a saturated brine (50 ml×2), dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue ispurified by silica gel column chromatography (eluent:chloroform/methanol) to give2-(3-bromophenoxy)-3-[3-(3,5-dimethoxypyridin-4-yl)propoxyl]pyridine,which is further treated with fumaric acid to give the title compound(1.26 g), m.p. 106-154° C.

Example 20 Preparation of2-(3-bromobenzyl)-3-[3-(3,5-dimethoxypyridin-4-yl)propoxy]pyridine.1.2oxalate

2-(3-Bromobenzyl)-3-pyridinol obtained in Reference Example 20 and3-(3,5-dimethoxypyridin-4-yl)-1-propanol obtained in Example 1 aretreated in a similar manner as in Example 19 to give2-(3-bromobenzyl)-3-[3-(3,5-dimethoxypyridin-4-yl)propoxy]pyridine,which is further treated with oxalic acid to give the title compound(1.27 g), m.p. 153-165° C. (recrystallized from ethanol).

Example 21 Preparation of2-phenoxy-3-[3-(3,5-dichloropyridin-4-yl)propoxy]pyridine

2-Phenoxy-3-pyridinol obtained in Reference Example 12 and3-(3,5-dichloropyridin-4-yl)-1-propanol obtained in Reference Example 23are treated in a similar manner as in Example 19 to give the titlecompound as a colorless oil.

¹H-NMR (200 MHz, CDCl₃, δ ppm): 2.05-2.21 (m, 2H), 3.11 (t, 2H, J=7 Hz),4.15 (t, 2H, J=7 Hz), 6.97 (dd, 1H, J=5 Hz, 8 Hz), 7.07-7.27 (m, 4H),7.33-7.43 (m, 2H) 7.77 (dd, 1H, J=2 Hz, 5 Hz), 8.41 (s, 2H)

Example 22 Preparation of2-(3-chlorophenoxy)-3-[3-(3-cyanopyridin-4-yl)propoxy]pyridine

2-(3-Chlorophenoxy)-3-pyridinol obtained in Reference Example 14 and3-(3-cyanopyridin-4-yl)-1-propanol obtained in Reference Example 34 aretreated in a similar manner as in Example 19 to give the title compound,m.p. 146-150° C.

Example 23 Preparation of2-(3-chlorophenoxy)-3-[3-(3-ethoxycarbonylpyridin-4-yl)propoxy]pyridine.1.3fumarate

2-(3-Chlorophenoxy)-3-pyridinol obtained in Reference Example 14 and3-(3-ethoxycarbonylpyridin-4-yl)-1-propanol obtained in ReferenceExample 35 are treated in a similar manner as in Example 19 to give2-(3-chlorophenoxy)-3-[3-(3-ethoxycarbonylpyridin-4-yl)propoxy]pyridine,which is further treated with fumaric acid to give the title compound,m.p. 140-164° C. (recrystallized from isopropyl ether).

Example 24 Preparation of2-(3-chlorophenoxy)-3-[3-(3-carboxypyridin-4-yl)propoxy]pyridine

2-(3-Chlorophenoxy)-3-[3-(3-ethoxycarbonylpyridin-4-yl)propoxy]pyridine(1.0 g, 2.4 mmol) obtained in Example 23 is dissolved in methanol (50ml), and thereto is added a 1M aqueous sodium hydroxide solution (3.0ml), and the mixture is heated under reflux for 2 hours. The methanol isevaporated under reduced pressure, and the pH value of the residue isadjusted to pH 4 with a 1M aqueous hydrochloric acid solution, and themixture is extracted with chloroform/tetrahydrofuran (1:1) (50 ml×2),dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue is recrystallized from ethanol/diethyl ether togive the title compound (0.9 g) as colorless crystals, m.p. 142-144° C.

Example 25 Preparation of2-(3-chlorophenoxy)-3-[3-(3-aminopyridin-4-yl)propoxy]-pyridine

2-(3-Chlorophenoxy)-3-[3-(3-carboxypyridin-4-yl)propoxy]-pyridine (0.50g, 1.3 mmol) obtained in Example 24 is dissolved in tert-butanol (20ml), and thereto are added diphenylphosphoryl azide (0.42 ml, 2.0 mmol)and triethylamine (0.27 ml, 2.0 mmol), and the mixture is heated underreflux for 8 hours. The reaction is quenched with a saturated brine (50ml), and the reaction solution is extracted with ethyl acetate (50ml×2). The organic layer is washed with a saturated brine (30 ml×2),dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue is dissolved in methylene chloride (10 ml), andthereto is added trifluoroacetic acid (5 ml), and the mixture is stirredat 25° C. for 30 minutes. The reaction solution is concentrated underreduced pressure, and to the residue is added a saturated aqueous sodiumhydrogen carbonate solution (50 ml), and the mixture is extracted withethyl acetate (50 ml×2). The organic layer is washed with a saturatedbrine (30 ml×2), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue is purified by silicagel column chromatography (eluent; chloroform/methanol), and furtherrecrystallized from diethyl ether to give the title compound (0.23 g) ascolorless crystals, m.p. 140-142° C.

Example 26 Preparation of2-(3-bromophenylthio)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine

3-(3-Methoxymethoxypyridin-4-yl)-1-propanol (1.59 g, 9.2 mmol) obtainedin Example 2 and triphenylphosphine (2.78 g, 10.6 mmol) are dissolved inTHF (40 ml), and thereto are successively added with stirringdiisopropyl azodicarboxylate (1.85 g, 9.2 mmol) and2-(3-bromophenylthio)-3-pyridinol (2.00 g, 7.1 mmol) obtained inReference Example 1 under ice-cooling. The mixture is stirred at roomtemperature for 30 minutes, and the reaction solution is concentratedunder reduced pressure. To the residue is added ethyl acetate (50 ml),and the mixture is extracted with a 10% aqueous hydrochloric acidsolution (50 ml×2). The pH value of the aqueous layer is adjusted to pH12 with potassium carbonate, and the mixture is extracted with ethylacetate (100 ml×2). The organic layer is washed with a saturated brine(50 ml×2), dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. To the residue are added ethanol (200 ml) and a15% aqueous hydrochloric acid solution (10 ml), and the mixture isheated under reflux for 30 minutes. The reaction solution isconcentrated under reduced pressure, neutralized with a saturatedaqueous sodium hydrogen carbonate solution, and extracted with ethylacetate (100 ml×2). The organic layer is washed with a saturated brine(50 ml×2), dried over anhydrous magnesium sulfate, and concentratedunder reduced pressure. The residue is purified by silica gel columnchromatography (eluent: chloroform/ethyl acetate), and furtherrecrystallized from diethyl ether to give the title compound (1.98 g) ascolorless crystals, m.p. 169-171° C.

Example 27 Preparation of2-(3-acetylphenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine

2-(3-Acetylphenoxy)-3-pyridinol obtained in Reference Example 17 istreated in a similar manner as in Example 26 to give the title compoundas colorless crystals, m.p. 101-102° C.

Example 28 Preparation of2-(3-cyanophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine

2-(3-Cyanophenoxy)-3-pyridinol obtained in Reference Example 16 istreated in a similar manner as in Example 26 to give the title compoundas colorless crystals, m.p. 84-86° C.

Example 29 Preparation of2-(3-ethoxycarbonylphenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine.0.5fumarate

2-(3-Ethoxycarbonylphenoxy)-3-pyridinol obtained in Reference Example 18is treated in a similar manner as in Example 26 to give the titlecompound as colorless crystals, m.p. 76-79° C.

Example 30 Preparation of2-phenoxy-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine

2-Phenoxy-3-pyridinol obtained in Reference Example 12 is treated in asimilar manner as in Example 26 to give the title compound as colorlesscrystals, m.p. 163-165° C.

Example 31 Preparation of2-(3-chlorophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine

3-(3-Methoxymethoxypyridin-4-yl)-1-propanol (9.11 g, 52.6 mmol) obtainedin Example 2 and triphenylphosphine (14.8 g, 56.5 mmol) are dissolved inTHF (100 ml), and thereto are successively added with stirringdiisopropyl azodicarboxylate (10.6 g, 52.6 mmol) and a solution of2-(3-chlorophenoxy)-3-pyridinol (9.65 g, 43.5 mmol) obtained inReference Example 14 in THF (100 ml) under ice-cooling. The mixture isfurther stirred at 50° C. for 30 minutes, and the reaction solution isconcentrated under reduced pressure. To the residue is added ethylacetate (150 ml), and the mixture is extracted with a 10% aqueoushydrochloric acid solution (150 ml×2). The pH value of the aqueous layeris adjusted to pH 12 with potassium carbonate, and the mixture isextracted with ethyl acetate (200 ml×2). The organic layer is washedwith a saturated brine (50 ml×2), dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. To the residue areadded ethanol (500 ml) and a 15% aqueous hydrochloric acid solution (100ml), and the mixture is heated under reflux for 30 minutes. The reactionsolution is concentrated under reduced pressure, and the residue isneutralized with a saturated aqueous sodium hydrogen carbonate solution,and extracted with ethyl acetate (300 ml×2). The organic layer is washedwith a saturated brine (50 ml×2), dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue ispurified by silica gel column chromatography (eluent: hexane/ethylacetate), and further recrystallized from diethyl ether/isopropyl etherto give the title compound (8.09 g) as colorless crystals, m.p. 109-110°C.

Example 32 Preparation of2-(3-bromophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine

3-(3-Methoxymethoxypyridin-4-yl)-1-propanol (2.50 g, 12.7 mmol) obtainedin Example 2 and triphenylphosphine (4.50 g, 17.0 mmol) are dissolved inTHF (40 ml), and thereto are successively added with stirringdiisopropyl azodicarboxylate (3.00 g, 15.0 mmol) and2-(3-bromophenoxy)-3-pyridinol (2.50 g, 9.4 mmol) obtained in ReferenceExample 11 under ice-cooling. The mixture is further stirred at 40° C.for 30 minutes, and the reaction solution is concentrated under reducedpressure. To the residue is added ethyl acetate (50 ml), and the mixtureis extracted with a 10% aqueous hydrochloric acid solution (50 ml×2).The pH value of the aqueous layer is adjusted to pH 12 with potassiumcarbonate, and the mixture is extracted with ethyl acetate (100 ml×2).The organic layer is washed with a saturated brine (50 ml×2), dried overanhydrous magnesium sulfate, and concentrated under reduced pressure. Tothe residue are added ethanol (200 ml) and a 47% aqueous hydrobromicacid solution (20 ml), and the mixture is heated under reflux for 30minutes. The reaction solution is concentrated under reduced pressure,and neutralized with a saturated aqueous sodium hydrogen carbonatesolution, and extracted with ethyl acetate (100 ml×2). The organic layeris washed with a saturated brine (50 ml×2), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residueis purified by silica gel column chromatography (eluent: hexane/ethylacetate/ethanol), recrystallized from ethanol/diethyl ether to give thetitle compound (3.10 g) as colorless crystals, m.p. 116-118° C.

Example 33 Preparation of2-(3-bromophenoxy)-3-[3-(3-methoxypyridin-4-yl)propoxy]pyridine

Sodium hydride (60% in mineral oil, 0.26 g, 6.5 mmol) is suspended inDMF (30 ml), and thereto is added2-(3-bromophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine (2.0 g,5.0 mmol) obtained in Example 32 at room temperature, and the mixture isstirred for 30 minutes. To the mixture is added methyl iodide (0.78 g,0.34 mmol) under ice-cooling, and the mixture is further stirred for 30minutes. To the reaction solution is added ethyl acetate (250 ml), andthe organic layer is washed with a saturated brine (50 ml×2), dried overanhydrous magnesium sulfate, and concentrated under reduced pressure.The residue is purified by basic silica gel column chromatography(eluent: chloroform/ethyl acetate), and recrystallized from diethylether to give the title compound (0.75 g) as colorless crystals, m.p.134-136° C.

Example 34 Preparation of2-(3-tetrazolylphenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine

2-(3-Cyanophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine (0.85 g,2.5 mmol) obtained in Example 28 is dissolved in DMF (10 ml), andthereto are added sodium azide (0.20 g, 3.0 mmol) and ammonium chloride(0.16 g, 3.0 mmol). The mixture is stirred at 130° C. for one hour, andthe reaction solution is concentrated under reduced pressure. Theresidue thus obtained is purified by silica gel column chromatography(eluent: acetic acid/ethanol), and recrystallized from ethanol to givethe title compound (0.31 g) as pale brown crystals, m.p. 220-240° C.(decomposed).

Example 35 Preparation of2-(3-bromophenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine

2-Bromo-3-[3-(pyridin-4-yl)propoxy]pyridine (1.0 g, 3.4 mmol) obtainedin Reference Example 27 and 3-bromophenol (0.87 g, 5.0 mmol) aredissolved in DMF (10 ml), and thereto are added potassium carbonate (1.4g, 10 mol) and cuprous bromide (0.72 g, 5.0 mmol). The mixture is heatedunder reflux at 140° C. for 1.5 hours. After being allowed to cool, tothe reaction solution is added ethyl acetate (100 ml), and the organiclayer is washed with a saturated brine (50 ml×2), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residueis purified by silica gel column chromatography (eluent: ethylacetate/hexane), and recrystallized from diethyl ether to give the titlecompound (0.80 g) as colorless crystals, m.p. 111-113° C.

Examples 36 to 42

The corresponding starting compounds are treated in a similar manner asin Example 35 to give the compounds of Examples 36 to 42 as listed inTable 5.

TABLE 5

Attaching Example A Position X¹ M.p. 36 NH 4 3-Br 111-113° C. 37 O 4 H97-98° C. 38 O 4 3-CF₃ 62-63° C. 39 O 4 3-F 117-118° C. 40 O 3 3-Br46-48° C. 41 O 4 3-CN 112-113° C. 42 O 3 H 119-131° C. (dihydrochloride)

Example 43 Preparation of2-(3,5-dichlorophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine

2-Bromo-3-[3-(3-methoxymethoxypyridin-4-yl)propoxy]pyridine (2.0 g, 5.7mmol) obtained in Reference Example 29 and 3,5-dichlorophenol (1.84 g,11.3 mmol) are dissolved in DMF (10 ml), and thereto are added potassiumcarbonate (1.4 g, 10 mol) and cuprous bromide (0.86 g, 6.0 mmol), andthe mixture is heated under reflux at 140° C. for 1.5 hours. After beingallowed to cool, to the reaction solution is added ethyl acetate (200ml), and the organic layer is washed with a saturated brine (50 ml×2),dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. To the residue are added ethanol (200 ml) and a 15% aqueoushydrochloric acid solution (20 ml), and the mixture is heated underreflux for 30 minutes. The reaction solution is concentrated underreduced pressure, and neutralized with a saturated aqueous sodiumhydrogen carbonate solution, and extracted with ethyl acetate (150ml×2). The organic layer is washed with a saturated brine (50 ml×2),dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue is purified by silica gel column chromatography(eluent: chloroform/methanol), and recrystallized from diethyl ether togive the title compound (1.19 g) as colorless crystals, m.p. 99-101° C.

Example 44 Preparation of2-(3-fluorophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine

2-Chloro-3-[3-(3-methoxymethoxypyridin-4-yl)propoxy]pyridine obtained inReference Example 28 and 3-fluorophenol are treated in a similar manneras in Example 43 to give the title compound as colorless crystals, m.p.68-70° C.

Example 45 Preparation of2-(3,5-dimethoxyphenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine

2-Bromo-3-[3-(3-methoxymethoxypyridin-4-yl)propoxy]pyridine obtained inReference Example 29 and 3,5-dimethoxyphenol are treated in a similarmanner as in Example 43 to give the title compound as colorlesscrystals, m.p. 172-178° C.

Example 46 Preparation of2-(3-bromoanilino)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine

2-Bromo-3-[3-(3-methoxymethoxypyridin-4-yl)propoxy]pyridine obtained inReference Example 29 and 3-bromoaniline are treated in a similar manneras in Example 43 to give the title compound as pale brown crystals, m.p.138-141° C.

Example 47 Preparation of2-phenoxy-3-[3-(3-methoxyethoxypyridin-4-yl)propoxy]pyridine.monofumarate

2-Methoxyethanol (0.08 g, 0.93 mmol) and triphenylphosphine (0.32 g, 1.2mmol) are dissolved in THF (20 ml), and thereto are successively addedwith stirring diisopropyl azodicarboxylate (0.17 g, 0.93 mmol) and2-phenoxy-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine (0.20 g, 0.62mmol) obtained in Example 30 under ice-cooling. The mixture is furtherstirred at 60° C. for one hour, and the reaction solution isconcentrated under reduced pressure. To the residue is added ethylacetate (50 ml), and the mixture is extracted with a 10% aqueoushydrochloric acid solution (50 ml×2). The pH value of the aqueous layeris adjusted to pH 12 with potassium carbonate, and the mixture isextracted with ethyl acetate (50 ml×2). The organic layer is washed witha saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue is purified by silicagel column chromatography (eluent: ethyl acetate/methanol) to give2-phenoxy-3-[3-(3-methoxyethoxypyridin-4-yl)propoxy]pyridine, which isfurther treated with fumaric acid to give the title compound (0.12 g),m.p. 120-123° C. (recrystallized from diethyl ether).

Example 48 Preparation of2-phenoxy-3-[3-(3-(2-hydroxyethoxy)pyridin-4-yl)propoxy]pyridine.monofumarate

Sodium hydride (60% in mineral oil, 0.08 g, 2.0 mmol) is suspended inDMF (5 ml), and thereto is added2-phenoxy-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine (0.20 g, 0.62mmol) obtained in Example 30 at room temperature, and the mixture isstirred for 30 minutes. To the mixture is added 2-methoxymethoxyethylbromide (0.32 g, 2.0 mmol) under ice-cooling, and the mixture is stirredat 50° C. for 30 minutes. To the reaction solution is added chloroform(100 ml), and the mixture is washed with a saturated brine (50 ml×2),dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. To the residue are added ethanol (20 ml) and a 35% aqueoushydrochloric acid solution (2 ml), and the mixture is stirred at 60° C.for 30 minutes. The pH value of the reaction solution is adjusted to pH10 with a saturated aqueous sodium hydrogen carbonate solution, and themixture is extracted with chloroform (50 ml×2), washed with a saturatedbrine (50 ml×2), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue is purified by silicagel column chromatography (eluent: chloroform/methanol) to give2-phenoxy-3-[3-(3-(2-hydroxyethoxy)pyridin-4-yl)propoxy]pyridine, whichis further treated with fumaric acid to give the title compound (0.17g), m.p. 129-132° C. (recrystallized from ethanol/isopropyl ether).

Example 49 Preparation of2-phenoxy-3-[3-(3-ethoxycarbonylmethoxy)pyridin-4-yl)propoxy]pyridine.difumarate

Sodium hydride (60% in mineral oil, 0.13 g, 3.1 mmol) is suspended inDMF (20 ml), and thereto is added2-phenoxy-3-13-(3-hydroxypyridin-4-yl)propoxy]pyridine (0.50 g, 1.6mmol) obtained in Example 30 at room temperature, and the mixture isstirred for 30 minutes. To the mixture is added ethyl bromoacetate (0.34ml, 3.1 mmol) under ice-cooling, and the mixture is stirred at roomtemperature for 20 minutes. To the reaction solution is added ethylacetate (100 ml), and the mixture is washed with a saturated brine (50ml×2), dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue is purified by silica gel columnchromatography (eluent: ethyl acetate/hexane) to give2-phenoxy-3-[3-(3-ethoxycarbonylmethoxy)pyridin-4-yl)propoxy]pyridine,which is further treated with fumaric acid to give the title compound(0.22 g), m.p. 130-140° C. (recrystallized from ethanol/diethyl ether).

Example 50 Preparation of2-phenoxy-3-[3-(3-carboxymethoxy)pyridin-4-yl)propoxy]pyridine.monofumarate

2-Phenoxy-3-[3-(3-ethoxycarbonylmethoxy)pyridin-4-yl)propoxy]pyridine(0.30 g, 0.74 mmol) obtained in Example 49 is dissolved in ethanol (10ml), and thereto is added a 1M aqueous sodium hydroxide solution (3 ml),and the mixture is heated under reflux for 30 minutes. The reactionsolution is concentrated under reduced pressure, and thereto is addedacetic acid (3 ml), and the mixture is extracted with ethyl acetate (50ml). The organic layer is washed with a saturated brine (20 ml×1), driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue is purified by silica gel column chromatography(eluent: chloroform/methanol) to give2-phenoxy-3-[3-(3-carboxymethoxy)pyridin-4-yl)propoxy]pyridine, which isfurther treated with fumaric acid to give the title compound (0.17 g),m.p. 167-174° C. (recrystallized from ethanol/water).

Example 51 Preparation of2-phenoxy-3-[3-(3-methoxypyridin-4-yl)propoxy]pyridine

Sodium hydride (60% in mineral oil, 0.04 g, 1.0 mmol) is suspended inDMF (10 ml), and thereto is added2-phenoxy-3-[3-(3-hydroxypyridin-4-yl)propoxylpyridine (0.20 g, 0.62mmol) obtained in Example 30 at room temperature, and the mixture isstirred for 30 minutes. To the mixture is added methyl iodide (0.06 ml,1.0 mmol) under ice-cooling, and the mixture is stirred for 10 minutes.To the reaction solution is added ethyl acetate (50 ml), and the mixtureis washed with a saturated brine (30 ml×2), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residueis purified by silica gel column chromatography (eluent:chloroform/methanol), and recrystallized from isopropyl ether to givethe title compound (0.09 g) as colorless crystals, m.p. 101-102° C.

Example 52 Preparation of2-(3-carboxyphenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine

2-(3-Cyanophenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine (1.15 g, 3.5mmol) obtained in Example 41 is dissolved in methanol (50 ml), andthereto is added a 30% aqueous sodium hydroxide solution (30 ml), andthe mixture is heated under reflux for 20 hours. The reaction solutionis concentrated under reduced pressure, and the pH value of the mixtureis adjusted to pH 3 with a 15% aqueous hydrochloric acid solution, andthe mixture is extracted with chloroform/THF (2:1) (50 ml×3). Theorganic layer is dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue is purified by silicagel column chromatography (eluent: chloroform/methanol), andcrystallized from diethyl ether to give the title compound (0.86 g) ascolorless crystals, m.p. 208-209° C.

Example 53 Preparation of2-(3-methoxycarbonylphenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine

2-(3-Carboxyphenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine (0.20 g, 0.57mmol) obtained in Example 52 is dissolved in methylene chloride (10 ml),and thereto are added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide.hydrochloride (0.13 g, 0.68 mmol) and methanol(0.10 ml), and the mixture is stirred at room temperature for 2 hours.To the reaction solution is added ethyl acetate (100 ml), and themixture is washed with a saturated brine (30 ml×2), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residueis purified by silica gel column chromatography (eluent:chloroform/methanol) to give the title compound (0.17 g) as colorlessoil.

¹H-NMR (200 MHz, CDCl₃, δ ppm): 2.07-2.24 (m, 2H), 2.59 (t, 2H, J=8 Hz),3.89 (s, 3H), 4.06 (t, 2H, J=6 Hz), 6.99 (dd, 1H, J=5 Hz, 8 Hz),7.10-7.14 (m, 2H), 7.20 (dd, 1H, J=2 Hz, 8 Hz), 7.35 (ddd, 1H, J=1 Hz, 2Hz, 8 Hz), 7.47 (t, 1H, J=8 Hz), 7.76 (dd, 1H, J=2Hz, 5Hz), 7.77-7.80(m, 1H, J=2 Hz), 7.86 (dt, 1H, J=1 Hz, 8 Hz), 8.47-8.51 (m, 2H)

Example 54 Preparation of2-(3-chlorophenoxy)-3-[3-(3-acetoxypyridin-4-yl)propoxy]pyridine.monofumarate

2-(3-Chlorophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine (1.0 g,2.8 mmol) obtained in Example 31 is dissolved in pyridine (3 ml), andthereto is added acetic anhydride (1.3 ml, 14 mmol), and the mixture isstirred at room temperature for 5 hours. To the reaction solution isadded ethyl acetate (100 ml), and the mixture is washed with a saturatedbrine (30 ml×2), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue is purified by silicagel column chromatography (eluent: ethyl acetate/hexane) to give2-(3-chlorophenoxy)-3-[3-(3-acetoxypyridin-4-yl)propoxy]pyridine, whichis further treated with fumaric acid to give the title compound (1.07g), m.p. 107-126° C. (recrystallized from diethyl ether).

Example 55 Preparation of2-(3-bromophenoxy)-3-[3-(3-acetoxypyridin-4-yl)propoxy]pyridine.1.5oxalate

2-(3-Bromophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine obtainedin Example 32 is treated in a similar manner as in Example 54 to givethe title compound, m.p. 110-112° C.

Example 56 Preparation of2-phenoxy-3-[3-(3-acetoxypyridin-4-yl)propoxy]pyridine

2-Phenoxy-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine obtained inExample 30 is treated in a similar manner as in Example 54 to give thetitle compound, m.p. 79-80° C.

Example 57 Preparation of2-(3-bromobenzyl)-3-[3-(3-acetoxypyridin-4-yl)propoxy]pyridine.1.5fumarate

2-(3-Bromobenzyl)-3-pyridinol obtained in Reference Example 20 istreated in a similar manner as in Example 26 to give2-(3-bromobenzyl)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine (m.p.138-139° C.), which is further treated in a similar manner as in Example54 to give the title compound, m.p. 122-128° C.

Example 58

Preparation of2-(3-bromophenoxy)-3-[3-(3-hydroxy-5-methoxypyridin-4-yl)propoxy]pyridine.0.5fumarate

and

Example 59 Preparation of2-(3-bromophenoxy)-3-[3-(3,5-dihydroxypyridin-4-yl)propoxy]pyridine.0.5fumarate

A mixture of 2-(3-bromophenoxy)-3-f3-(3,5-dimethoxypyridin-4-yl)propoxy]pyridine (3.15 g, 7.1 mmol)obtained in Example 19 and pyridine.hydrochloride (8.0 g) is stirred at180° C. for 1.5 hours. After being allowed to cool, to the mixture isadded a saturated aqueous sodium hydrogen carbonate solution (100 ml),and the mixture is extracted with ethyl acetate (100 ml×3). The organiclayer is washed with a saturated brine (50 ml×2), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residueis purified by silica gel column chromatography (eluent:chloroform/methanol) to give2-(3-bromophenoxy)-3-[3-(3-hydroxy-5-methoxypyridin-4-yl)propoxy]pyridineand 2-(3-bromophenoxy)-3-[3-(3,5-dihydroxypyridin-4-yl)propoxy]pyridine,which are individually treated with fumaric acid to give2-(3-bromophenoxy)-3-[3-(3-hydroxy-5-methoxypyridin-4-yl)propoxy]pyridine.0.5fumarate (1.00 g) [m.p. 157-161° C. (recrystallized from ethanol/diethylether)] and2-(3-bromophenoxy)-3-[3-(3,5-dihydroxypyridin-4-yl)propoxy]pyridine.0.5fumarate (1.36 g) [m.p. 184-189° C. (recrystallized from ethanol)],respectively.

Example 60 Preparation of2-(3-acetylphenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine.0.5 fumarate

2-(3-Cyanophenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine (0.50 g, 1.5mmol) obtained in Example 41 is dissolved in THF (10 ml), and thereto isadded a solution of methyl lithium in diethyl ether (2.7 ml, 3.8 mmol)at −70° C., and the mixture is stirred for 10 minutes. The mixture iswarmed to 0° C. over a period of time for 30 minutes, and the reactionis quenched with a saturated brine. The reaction solution is extractedwith ethyl acetate (100 ml), and the organic layer is washed with asaturated brine (50 ml×2), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue is purified by silicagel column chromatography (eluent: chloroform/methanol) to give2-(3-acetylphenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine, which isfurther treated with fumaric acid to give the title compound (0.20 g),m.p. 117-119° C. (recrystallized from ethanol/diethyl ether).

Example 61 Preparation of2-[3-(1-hydroxyethyl)phenoxy]-3-[3-(pyridin-4-yl)propoxy]pyridine.1.0fumarate

2-(3-Acetylphenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine (0.20 g, 0.3mmol) obtained in Example 60 is dissolved in methanol (10 ml), andthereto is added sodium borohydride (0.50 g, 13 mmol), and the mixtureis stirred at room temperature for 10 minutes. To the reaction solutionis added a saturated brine (50 ml), and the mixture is extracted withethyl acetate (100 ml). The organic layer is washed with a saturatedbrine (50 ml×2), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue is purified by silicagel column chromatography (eluent: chloroform/methanol) to give2-[3-(1-hydroxyethyl)phenoxy]-3-[3-(pyridin-4-yl)propoxy]pyridine, whichis further treated with fumaric acid to give the title compound (0.06g), m.p. 93-97° C. (recrystallized from ethanol/diethyl ether).

Example 62 Preparation of 3-(3-hydroxypyridin-4-yl)-1-propanol

3-(3-Methoxymethoxypyridin-4-yl)-1-propanol (3.67 g, 18.6 mmol) obtainedin Example 2 is dissolved in ethanol (100 ml), and thereto is added a15% aqueous hydrochloric acid solution (20 ml), and the mixture isheated under reflux for 30 minutes. The reaction solution isconcentrated under reduced pressure, and the residue is purified bysilica gel column chromatography (eluent: hexane/ethyl acetate), andfurther recrystallized from diethyl ether to give the title compound(2.08 g) as colorless crystals, m.p. 123-126° C.

Example 63 Preparation of3-[3-(2,6-dimethoxybenzolyloxy)pyridin-4-yl]-1-propanol

(i) 3-(3-Hydroxypyridin-4-yl)-1-propanol (1.00 g, 6.53 mmol) obtained inExample 62 is dissolved in THF, and thereto are added dihydropyrane (5.0ml, 55 mmol), D,L-camphore-10-sulfonic acid (1.00 g, 4.30 mmol), and themixture is heated under reflux for 20 minutes. The reaction solution ispoured into an aqueous sodium hydrogen carbonate solution, and themixture is extracted with ethyl acetate (200 ml×2), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residueis purified by silica gel column chromatography (eluent: hexane/ethylacetate) to give 3-hydroxy-4-(3-tetrahydropyranyloxypropyl)pyridine ascolorless oil.

(ii) The oily product obtained in the above is dissolved in pyridine (12ml), and thereto is added 2,6-dimethoxybenzolyl chloride (4.6 g, 7.4mmol), and the mixture is stirred at room temperature for 10 minutes. Tothe reaction solution is added ethyl acetate (300 ml), and the mixtureis successively washed with a saturated aqueous sodium hydrogencarbonate solution (50 ml×2), a saturated aqueous cuprous sulfatesolution (50 ml×2) and a saturated brine (50 ml×2), dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. The residueis purified by silica gel column chromatography (eluent: hexane/ethylacetate) to give3-(2,6-dimethoxybenzolyloxy)-4-(3-tetrahydropyranyloxypropyl)pyridine asa colorless oil.

(iii) The oily product obtained in (ii) is added to methanol (100 ml)and a 10% aqueous hydrochloric acid solution (5 ml), and the mixture isstirred at 40° C. for 30 minutes. After cooling, the reaction solutionis neutralized with a saturated aqueous sodium hydrogen carbonatesolution, extracted with ethyl acetate (400 ml), and washed with asaturated brine (50 ml×2). The mixture is dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue isrecrystallized from diethyl ether to give the title compound (0.80 g) ascolorless crystals, m.p. 117-118° C.

Example 64 Preparation of 3-(5-benzyloxypyridin-3-yl)propanol

3-(5-Benzyloxypyridin-3-yl)propenoic acid ethyl ester (2.65 g, 9.4 mmol)obtained in Reference Example 36 is dissolved in ethanol (150 ml), andthereto is added sodium borohydride (3.54 g, 94 mmol), and the mixtureis heated under reflux for 3 hours. The reaction solution is evaporatedunder reduced pressure, and to the residue is added water (100 ml) andthe mixture is extracted with ethyl acetate (100 ml×2). The extract iswashed with a saturated brine (50 ml×2), dried over anhydrous magnesiumsulfate, and concentrated under reduced pressure. The residue ispurified by silica gel column chromatography (eluent: ethylacetate/hexane) to give the title compound (1.8 g) as a pale yellow oil.

¹H-NMR (300 MHz, CDCl₃, δ ppm): 1.80-2.10 (m, 3H), 2.71 (t, 2H, J=8 Hz),3.66 (t, 2H, J=6 Hz), 5.10 (s, 2H), 7.11 (t, 1H, J=2 Hz), 7.30-7.48 (m,5H), 8.09 (d, 1H, J=2 Hz), 8.21 (d, 1H, J=2 Hz)

Example 65

Preparation of2-(3-chlorophenoxy)-3-[3-(5-hydroxypyridin-3-yl)propoxy]pyridine

2-(3-Chlorophenoxy)-3-pyridinol obtained in Reference Example 14 and3-(5-benzyloxypyridin-3-yl)-1-propanol obtained in Example 64 aretreated in a similar manner as in Example 3 to give2-(3-chlorophenoxy)-3-[3-(5-benzyloxypyridin-3-yl)propoxy]pyridine.

2-(3-Chlorophenoxy)-3-[3-(5-benzyloxypyridin-3-yl)propoxy]pyridine (2.5g, 5.6 mmol) thus obtained is dissolved in ethanol (100 ml), and theretois added conc. hydrochloric acid (100 ml), and the mixture is heatedunder reflux. At 5 hours thereafter and at 10 hours thereafter, conc.hydrochloric acid (50 ml×2) is added to the mixture, and then themixture is refluxed for 20 hours, and allowed to cool. The mixture isneutralized with an aqueous sodium hydrogen carbonate solution, andextracted with ethyl acetate (100 ml×2). The extract is washed with asaturated brine (50 ml×2), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue is purified by silicagel column chromatography (eluent: ethyl acetate/hexane), andrecrystallized from ethyl acetate/hexane to give the title compound (1.3g) as colorless crystals, m.p. 148-149° C.

Example 66 Preparation of3-(3-ethoxycarbonyl-5-methoxypyridin-4-yl)-1-propanol

1-(3-Cyano-5-methoxypyridin-4-yl)-3-benzyloxypropane (2.3 g, 8 mmol)obtained in Reference Example 41 is dissolved in ethanol (35 ml), andthereto is added a 10% aqueous sodium hydroxide solution (15 ml), andthe mixture is stirred at 70° C. for 1.5 hours. The mixture isneutralized with conc. hydrochloric acid, and the reaction solution isconcentrated under reduced pressure. The residue thus obtained isdissolved in a 30% solution of hydrochloric acid in ethanol (50 ml), andthe mixture is heated under reflux for 14 hours. The mixture isneutralized with sodium hydrogen carbonate, and the reaction solution isconcentrated again under reduced pressure. The resultant is extractedwith ethyl acetate (200 ml), washed with a saturated brine (50 ml×2),dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue is purified by silica gel column chromatography(eluent: ethyl acetate/hexane), and recrystallized from ether to givethe title compound (0.60 g) as colorless crystals, m.p. 85-89° C.

Example 67 Preparation of2-(3-chlorophenoxy)-3-[3-(3-ethoxycarbonyl-5-methoxypyridin-4-yl)propoxy]pyridine

2-(3-Chlorophenoxy)-3-pyridinol obtained in Reference Example 14 and3-(3-ethoxycarbonyl-5-methoxypyridin-4-yl)-1-propanol obtained inExample 66 are treated in a similar manner as in Example 3 to give thetitle compound, m.p. 82-83° C.

Example 68 Preparation of2-(3-chlorophenoxy)-3-[3-(3-carboxyl-5-methoxypyridin-4-yl)propoxy]pyridine

2-(3-Chlorophenoxy)-3-[3-(3-ethoxycarbonyl-5-methoxypyridin-4-yl)propoxy]pyridine(4.4 g, 10 mmol) obtained in Example 67 is dissolved in ethanol (40 ml),and thereto is added a solution of sodium hydroxide (0.80 g, 20 mmol) inwater (5 ml), and the mixture is stirred at 70° C. for 30 minutes. Themixture is concentrated under reduced pressure, and thereto is addedwater (50 ml), and further thereto is added dropwise acetic acid (3 ml)with stirring. The precipitated crystals are collected by filtration,washed with water, and dried to give the title compound (3.6 g) ascolorless crystals, m.p. 166-168° C.

Example 69 Preparation of2-(3-chlorophenoxy)-3-[3-(3-amino-5-hydroxypyridin-4-yl)propoxy]pyridine.1.0fumarate

2-(3-Chlorophenoxy)-3-[3-(3-carboxyl-5-methoxypyridin-4-yl)propoxy]pyridine(3.8 g, 9.2 mmol) obtained in Example 68 is suspended in toluene (40ml), and thereto is added triethylamine (3.5 g, 35 mmol), and furtherthereto are added diphenylphosphoryl azide (4.1 g, 15 mmol) at 70° C.for 30 minutes. Then, p-methoxybenzyl alcohol (3.5 g, 25 mmol) is addedto the mixture, and 30 minutes thereafter, ethyl acetate (300 ml) isadded to the reaction solution. The mixture is washed with a saturatedaqueous sodium hydrogen carbonate solution and a saturated brine (50ml×2), dried over anhydrous magnesium sulfate, and concentrated underreduced pressure. The residue is purified by silica gel columnchromatography (eluent: ethyl acetate/hexane) to give2-(3-chlorophenoxy)-3-{3-[3-(4-methoxybenzyloxycarbonyl)amino-5-hydroxypyridin-4-yl]propoxy}pyridine (3.5 g)as a pale yellow oil.

The oily product thus obtained is mixed with pyridine hydrochloride (30g), and the mixture is stirred for melting at 150° C. for 1.5 hours.After being allowed to cool, water (100 ml) is added to the mixture, andthe mixture is neutralized with sodium hydrogen carbonate, and extractedwith chloroform (100 ml×4). The chloroform layers are combined, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue is purified by basic silica gel columnchromatography (eluent: ethanol/chloroform) to give2-(3-chlorophenoxy)-3-[3-(3-amino-5-hydroxypyridin-4-yl)propoxy]pyridine(0.85 g) as a pale brown oil, which is further treated with fumaric acidto give the title compound (0.53 g), m.p. 75-90° C. (recrystallized fromethyl acetate).

Example 70 Preparation of2-(3-chlorophenoxy)-3-[3-(3-methylsulfonylaminopyridin-4-yl)propoxy]pyridine

2-(3-Chlorophenoxy)-3-[3-(3-aminopyridin-4-yl)propoxy]pyridine (0.15 g,0.42 mmol) obtained in Example 25 is dissolved in methylene chloride (5ml) and pyridine (0.34 ml), and thereto is added ethylsulfonyl chloride(0.04 ml, 0.50 mmol) under ice-cooling, and the mixture is stirred for 3hours. To the mixture is added ice-water (20 ml), and the mixture isextracted with ethyl acetate (50 ml×2). The organic layer is washed witha saturated aqueous sodium hydrogen carbonate solution (20 ml×2) and asaturated brine (20 ml×2), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue is purified by basicsilica gel column chromatography (eluent: chloroform/methanol), andfurther recrystallized from diethyl ether to give the title compound(0.07 g) as colorless crystals, m.p. 131-133° C.

Example 71 Preparation of 3-(3-chloro-5-methoxypyridin-4-yl)-1-propanol

1-(3-Chloro-5-methoxypyridin-4-yl)-3-(tetrahydropyranyl-2-oxy)propane(4.0 g, 14 mmol) obtained in Reference Example 38 is dissolved inethanol (100 ml), and thereto is added a 15% aqueous hydrochloric acidsolution (3 ml), and the mixture is stirred at 60° C. for 20 minutes.The reaction solution is concentrated under reduced pressure, and theresidue thus obtained is purified by basic silica gel columnchromatography (eluent: ethyl acetate) to give the title compound (2.2g) as a pale yellow oil.

¹H-NMR (300 MHz, CDCl₃, δ ppm): 1.77 (t, 1H, J=6 Hz), 1.80-1.89 (m, 2H),2.89 (t, 2H, J=7 Hz), 3.63 (q, 2H, J=7 Hz), 3.95 (s, 3H), 8.12 (s, 1H),8.23 (s, 1H)

Example 72 Preparation of2-(3-chlorophenoxy)-3-[3-(3-chloro-5-methoxypyridin-4-yl)propoxy]pyridine

2-(3-Chlorophenoxy)-3-pyridinol obtained in Reference Example 14 and3-(3-chloro-5-methoxypyridin-4-yl)-1-propanol obtained in Example 71 istreated in a similar manner as in Example 3 to give the title compound(2.7 g) as colorless oil.

¹H-NMR (300 MHz, CDCl₃, δ ppm): 2.03-2.15 (m, 2H), 2.95 (t, 2H, J=7 Hz),3.87 (s, 3H), 4.08 (t, 2H, J=7 Hz), 6.97-7.06 (m, 2H), 7.11-7.17 (m,2H), 7.20 (dd, 1H, J=2 Hz, 8 Hz), 7.26-7.33 (m, 1H), 7.76 (dd, 1H, J=2Hz, 5 Hz), 8.09 (s,1H), 8.21 (s,1H)

Example 73 Preparation of2-(3-chlorophenoxy)-3-[3-(3-chloro-5-hydroxypyridin-4-yl)propoxy]pyridine

2-(3-Chlorophenoxy)-3-[3-(3-chloro-5-methoxypyridin-4-yl)propoxy]pyridine(8.5 g, 21 mmol) obtained in Example 72 and pyridine.hydrochloride (100g, 0.86 mol) are mixed, and the mixture is stirred for melting at 150°C. for one hour. To the mixture is added ice-water (300 ml), and themixture is neutralized with sodium hydrogen carbonate, and extractedwith ethyl acetate (100 ml×3). The organic layer is washed with asaturated aqueous sodium hydrogen carbonate solution (50 ml×2) and asaturated brine (50 ml×2), dried over anhydrous magnesium sulfate, andconcentrated under reduced pressure. The residue is purified by basicsilica gel column chromatography (eluent: ethanol/ethyl acetate), andfurther recrystallized from diethyl ether/diisopropyl ether to give thetitle compound (5.6 g) as colorless crystals, m.p. 95-96° C.

Preparation: Production of Tablets

The following components are mixed and kneaded in a conventional manner,and the mixture is granulated. The mixture is further compressed fortabletting to give 1,000 tablets (each 100 mg).2-(3-Chlorophenoxy)-3-[(3-hydroxypyridin-4-yl)propoxy]pyridine (thecompound of Example 31) (5 g),

Corn starch (25 g),

Lactose (54 g),

Crystalline cellulose (11 g),

Hydroxypropyl cellulose(3 g),

Light anhydrous silicic acid (1 g), and

Magnesium stearate (1 g).

INDUSTRIAL APPLICABILITY

The compounds (I) of the present invention show a potent PDE IVinhibitory activity as well as an excellent bronchodilating activity,and hence, they are widely useful as a PDE IV inhibitor in the treatmentor prophylaxis of allergic inflammatory diseases or organ inflammatorydiseases. Especially they are useful in the treatment or prophylaxis ofpulmonary diseases accompanied by airway obstruction such as asthma.

What is claimed is:
 1. A compound of the formula (I)

wherein A is an oxygen atom, a sulfur atom, CHR¹ or NR², R¹ and R² are a hydrogen atom or a lower alkyl group; X¹ and X² are the same or different and each a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, a lower alkyl group, a hydroxy-substituted lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, a lower acyl group, a lower acyloxy group, an amino group, a lower acylamino group, a carbamoyl group, a 5-tetrazolyl group, or a group which can be converted into a hydroxy group in vivo; Y¹ is a hydrogen atom or a lower alkyl group; Z¹ and Z² are the same or different and each a hydrogen atom, a halogen atom, a cyano group, a hydroxy group, a lower alkyl group, a hydroxy-substituted lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, a lower acyloxy group, an amino group, a mono- or di-lower alkylamino group, a lower acylamino group, a lower alkoxycarbonylamino group, a lower alkylsulfonylamino group, a carbamoyl group, a 5-tetrazolyl group, or a group which can be converted into a hydroxy group in vivo; and n is an integer of 2 to 4, or a pharmaceutically acceptable salt thereof.
 2. The compound according to claim 1, wherein A is an oxygen atom, a sulfur atom, CH₂ or NH, Z¹ and Z² are the same or different and each a hydrogen atom, a halogen atom, a hydroxy group, a lower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a mono- or di-lower alkylaminocarbonyl group, a lower acyloxy group, an amino group, a mono- or di-lower alkylamino group, a lower acylamino group, a lower alkoxycarbonylamino group, a lower alkylsulfonylamino group, a carbamoyl group, or a group which can be converted into a hydroxy group in vivo, or a pharmaceutically acceptable salt thereof.
 3. A compound of the formula (Ia):

wherein A¹ is an oxygen atom, a sulfur atom, CH₂ or NH; X¹¹ is a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxy group, a lower alkyl group, a hydroxy-substituted lower alkyl group, a halogeno-lower alkyl group, a lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxycarbonyl group, a mono- or di-lower alkylaminocarbonyl group, or a lower acyl group; X²¹ is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group; Y¹ is a hydrogen atom or a lower alkyl group; Z¹¹ and Z²¹ are the same or different and each a hydrogen atom, a halogen atom, a hydroxy group, a lower alkoxy group, a cyclo-lower alkoxy group, a hydroxy-substituted lower alkoxy group, a halogeno-lower alkoxy group, a lower alkoxy-substituted lower alkoxy group, a carboxy-substituted lower alkoxy group, a lower alkoxycarbonyl-substituted lower alkoxy group, a mono- or di-lower alkylaminocarbonyl group, a lower acyloxy group, an amino group, a mono- or di-lower alkylamino group, a lower acylamino group, a lower alkoxycarbonylamino group, a lower alkylsulfonylamino group, a carbamoyl group, or a group which can be converted into a hydroxy group in vivo, or a pharmaceutically acceptable salt.
 4. A compound which is selected from the group consisting of the following compounds: 2-phenoxy-3-[3-(pyridin-4-yl)propoxy]pyridine; 2-(3-bromophenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine; 2-(3-fluorophenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine; 2-(3-fluorophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine; 2-(3-chlorophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine; 2-(3-bromophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine; 2-(3-chlorophenoxy)-3-[3-(3-aminopyridin-4-yl)propoxy]pyridine; 2-phenoxy-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine; 2-phenoxy-3-[3-(3-acetoxypyridin-4-yl)propoxy]pyridine; 2-(3-chlorophenoxy)-3-[3-(3-acetoxypyridin-4-yl)propoxy]pyridine; 2-(3-chlorophenoxy)-3-[3-(3-chloro-5-hydroxypyridin-4-yl)propoxy]pyridine; 2-(3-chlorophenoxy)-3-[3-(3-hydroxypyridin-5-yl)propoxy]pyridine; 2-(3-chlorophenoxy)-3-[3-(3-amino-5-hydroxypyridin-4-yl)propoxy]pyridine; 2-(3-chlorophenoxy)-3-[3-(3-methylsulfonylaminopyridin-4-yl)propoxy]pyridine; and 2-(3-bromophenylthio)-3-(3-(pyridin-4-yl)propoxy]pyridine, or a pharmaceutically acceptable salt thereof.
 5. 2-(3-Chlorophenoxy)-3-[3-(3-hydroxypyridin-4-yl)propoxy]pyridine, or a pharmaceutically acceptable salt thereof.
 6. A pharmaceutical composition for inhibiting phosphodiesterase IV, which comprises an effective amount of a compound as set forth in any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent. 